Navigating the Next Step After Progression in ccRCC

When advanced clear cell renal cell carcinoma (ccRCC) progresses after first-line therapy, the treatment strategy must be reassessed based on disease course, prior treatment, and the patient's overall condition. In a virtual Case-Based Roundtable event, David Braun, MD, PhD, associate professor of Internal Medicine (Medical Oncology and Hematology) at Yale School of Medicine, and Jahan Aghalar, MD, medical oncologist/hematologist at New York Cancer & Blood Specialists/OneOncology, moderated a discussion with oncologists in the mid-Atlantic region, sharing perspectives on selecting second-line therapy following progression on first-line immunotherapy and tyrosine kinase inhibitor (TKI) treatment.

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CASE SUMMARY

• 61-year-old man, married, father of 2 grown children and 5 grandchildren who live nearby, active lifestyle (daily walks, golfs regularly)
• History of low-volume, indolent metastatic ccRCC, status post left nephrectomy and adrenalectomy
• Based on low-volume, indolent disease and patient preference – observation only
• 1.5 years postnephrectomy CT scan:
• New paratracheal lymph node (2.0 x 1.5 cm) and > 10 pulmonary nodules on CT
• Lung biopsy confirms metastatic ccRCC
• Labs: within normal limits
• ECOG performance status: 0
• The patient received first-line cabozantinib [(abometyx) plus nivolumab (Opdivo)
• Decrease or stabilization in metastatic lesions noted on follow up imaging
• He tolerated therapy well, with 1 interruption due to hypothyroidism on routine labs (treated with levothyroxine).
• 14 months after initiation of systemic therapy, the patient reported increasing back pain, mild nausea, weight loss, and new onset of persistent rib pain.
• Imaging confirms disease progression: growth of paratracheal lymph node (was 20 x 15 mm; now 25 x 28 mm), new mediastinal and hilar nodal involvement, new retroperitoneal nodes and new lytic osseous lesions
• ECOG performance status: 1

DISCUSSION QUESTIONS

• What are the goals of therapy for this patient going into the second line?
• Do certain factors influence your second-line regimen selection?
• Have you ever tried continuing / rechallenging with an ICI in a patient who had received a prior ICI?

Gabriel Jung, MD: [My considerations are] how effective it is and if the survival will benefit. The tolerance [and adverse effects] are an issue; after the patient gets to the second line, they're more beat up; they might be more fragile. ECOG [performance status is another consideration]. Obviously, if I can get these medications approved, there definitely needs to be an [National Comprehensive Cancer Network (NCCN)] guideline… But I think for me, really, it's the patient's ECOG status and tolerability, and that also includes the toxicity profile.

David Braun, MD, PhD: So that sort of balance; that makes a lot of sense.

As you're thinking about a lot of the challenges in the second line, is there something you find particularly challenging?

Eshan Patel, MD: I think tolerability is number 1. After having that first-line VEGF and immunotherapy, some of the patients are usually beat up or have some [adverse] effects... I have patients with colitis and some residual colitis from that combination.

Other than that, I think [another consideration is] data in terms of [comparative] survival benefit [between regimens]. If there are marginal data with more toxicity, I think I will stay away from that kind of combination.

Braun: Are there other things that you take into account? Something…that I haven't heard yet is the site of disease. Let's say, if someone has a brain metastasis or bone metastasis, do you think about one treatment or another, or do you try to switch mechanism of action?

Raghava Reddy Levaka Veera, MD: Obviously tolerability and NCCN guideline recommendation are important, but mechanism of action is [also] a big thing for me. I don't want to give a drug with the same mechanism of action once the patient progressed on the similar previous drug.

Tina Mayer, MD: One of the things we didn't touch upon is the nature of response to the second-line therapy in terms of depth and duration. I feel like with first line, you have this hope that you're maybe going to have a complete remission or a really durable response. But when you see someone progress—I think this was like 14, 15 months, outside of trials—you're not necessarily expecting to see these long-term, durable responses. And so, I think that the tolerability factor also plays in a lot with that vs your first-line regimen, where there's that optimism more so than in the second line.

Braun: I think you also bring up this idea which is important: the difference between clinical trials and real-life practice. On paper, the median duration of response for nivolumab-cabozantinib is 22 months.¹ In a clinical trial setting, most of these durations of response for immunotherapy[immunotherapy (IO) and tyrosine kinase inhibitor (TKI)] combinations are usually around 2 years, but when you bring it into the real world, where it's not the health of patients that are entering trials, you often see [cases] more like [this patient]: a year and change.

Tarun Wasil, MD: One of the things we can look into is prior experience—my colleagues' or my experiences with some of the medications. That also plays a role to some extent.

Yacoub Faroun, MD: I think you have to look at the patient—what they got as upfront therapy, IO-IO in such a patient, and the site of the metastases. I would choose second-line cabozantinib at 40 mg once a day because he’s never [had a] TKI before. He had bone metastases, which there is efficacy in bone metastases and liver metastases, and it is a different mechanism of action… Yes, belzutifan [Welireg] is approved; however, I can leave it for patient who has a VHL mutation. I send for next-generation sequencing [NGS] testing on the initial biopsy, or I do the germline testing if I don't have any tissue, just to see if I can start with some mutation that is actionable.

Braun: That's really helpful. One thing I'll highlight, because I think this is a point that comes up a lot, is the idea of mutation testing for belzutifan. Part of it is based on how it was approved initially, and the second part is actually based on [precision medicine] companies and how they report [results].

When belzutifan was originally approved, it was for a very small group of patients with germline Von Hippel-Lindau [VHL] syndrome, so they had to have germline inherited disease, and that was the approval.² But the second approval…is for all clear cell kidney cancer, specifically after a PD-1/PD-L1 inhibitor and a [VEGF] TKI, so the patient doesn't need a VHL mutation.³ The reason is, just about every sporadic clear cell has loss of VHL. That's almost a defining feature of kidney cancer; [over 90%] will lose one part of it from 3p loss, so they'll lose a chromosome copy, and the other copy gets lost either by mutation or methylation.⁴ That’s a long way of saying, even though the [NGS report] might say, “The [patient] has a VHL mutation; think about belzutifan,” You don't actually have to look for VHL mutations whether they have it or not. If they have clear cell kidney cancer, that's the key; it won't work for other types of kidney cancer, but for clear cell kidney cancer, it's going to be approved.

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DISCLOSURES: Braun previously disclosed serving a consulting or advisory role for Bristol-Myers Squibb, Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group, Insight Strategy, Schlesinger Associates, Exelixis, AVEO, Catenion, Cello Health, Aptitude Health, AbbVie, DLA Piper, Merck, Elephas Bio, CurIOS Therapeutics, Pfizer, Scholar Rock, Eisai, 2nd.MD, Compugen, Link Cell Therapies, Neomorph, Nimbus Therapeutics, Daiichi Sankyo, and Caris Life Sciences; and research funding from Exelixis and AstraZeneca.

Aghalar previously disclosed a consulting or advisory role for Bayer AG and Janssen Oncology, and serving on a speakers’ bureau for Janssen Oncology, Sanofi, and EMD Serono.

REFERENCES

1. Powles T, Burotto M, Escudier B, et al. Nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended follow-up from the phase III randomised CheckMate 9ER trial. ESMO Open. 2024;9(5):102994. doi:10.1016/j.esmoop.2024.102994

2. Fallah J, Brave MH, Weinstock C, et al. FDA Approval Summary: Belzutifan for von Hippel-Lindau Disease-Associated Tumors. Clin Cancer Res. 2022;28(22):4843-4848. doi:10.1158/1078-0432.CCR-22-1054

3. FDA approves belzutifan for advanced renal cell carcinoma. News release. US FDA. December 14, 2023. Accessed September 17, 2026. https://tinyurl.com/mr2d8z54

4. Hsieh JJ, Le VH, Oyama T, Ricketts CJ, Ho TH, Cheng EH. Chromosome 3p Loss-Orchestrated VHL, HIF, and Epigenetic Deregulation in Clear Cell Renal Cell Carcinoma. J Clin Oncol. Published online October 29, 2018. doi:10.1200/JCO.2018.79.2549