Adjuvant IO Exposure Complicates Treatment Selection for mRCC

As oncologists develop experience using combination regimens for metastatic clear cell renal cell carcinoma (RCC), patient-specific decisions on which therapy to use are becoming more common. During a virtual Case-Based Roundtable event, Kathryn E. Beckermann, MD, PhD, discussed key areas that still have an unclear impact in this setting. Beckermann, director of Genitourinary Clinical Research at Tennessee Oncology and instructor in medicine at the Rathmell Lab, Vanderbilt University School of Medicine in Nashville, asked participants about their perspectives on dose modification and how prior use of adjuvant immune checkpoint inhibitor therapy would affect their treatment approach.

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This article is part 2 of a 2-part series from a Case-Based Roundtable event.

CASE SUMMARY

• A 65-year-old man presented with back pain for past 6 months and hematuria for 1 week. ​
• Laboratory findings: hemoglobin 11.4 g/dL, lactate dehydrogenase 980 U/L, all others within normal limits​
• CT scan of chest, abdomen, and pelvis shows high-disease burden, including multiple mediastinal and hilar nodes, deposits in lower lobe of lung, enlarged axillary nodes, and enhancing mass in left renal parenchyma with renal vein infiltration; lytic destruction of L4 and L5 vertebrae, left superior pubic ramus, and right ischium ​
• Biopsy of renal mass and bone biopsy confirmed metastatic clear cell RCC.

DISCUSSION QUESTIONS

• How do the safety profiles of each regimen compare?​
• How often do you have to modify/interrupt/discontinue for toxicity?​
• What influences your decision to initiate therapy at a dose lower than the protocol dose?​

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Kathryn E. Beckermann, MD, PhD: How do you consider the safety profiles when you’re looking at each of the individual IO [immunotherapy] plus TKI [tyrosine kinase inhibitor] regimens? What’s your typical pattern for holding or modifying the each of the agents as a patient is experiencing toxicity?

Christopher Wee, MD: If I’m really worried about a patient, I’ll start with pembrolizumab [Keytruda] plus axitinib [Inlyta], given that short half-life. I always start the highest dose for all the other ones. You can technically go up. I’ve done that only in a minority of cases, because psychologically it’s challenging to say, “You’re feeling great, [but] let’s crank it up,” vs with the lenvatinib [Lenvima] plus pembrolizumab, if you start the highest, you can say, “There’s a good chance you’ll want to come down.” Then the patient [knows] something better is going to happen.

Kevin M. Gallagher, MD: That is always what I struggle with. I don’t want to turn somebody off and want to cancel the entire treatment plan if the adverse events are too intolerable. Trying to find that middle ground is somewhat challenging for me.

Beckermann: For those in the community, do you find it hard to make those dose modifications, to go from, if it’s axitinib, getting the individual pill vs the 5-mg tablet, or any issues?

Madhu V. Midathada, MD: There are no issues with access. I find it easier to start at a lower dose and then to escalate as tolerated. Of course, you take their comorbidities, their performance status, and their underlying immune-mediated or other problems into consideration while deciding on the treatment, but it just seems easier to dose escalate.

ALTERNATE SCENARIO:

• A 65-year-old man with a history of clear cell RCC, high disease burden, status post left nephrectomy and adrenalectomy, received adjuvant pembrolizumab.
• One year later, he presented with back pain for past 6 months and hematuria for 1 week. ​
• Laboratory findings: hemoglobin 11.4 g/dL, lactate dehydrogenase 980 U/L, all others within normal limits​
• CT scan of chest, abdomen, and pelvis shows high-disease burden, including multiple mediastinal and hilar nodes, deposits in lower lobe of lung, enlarged axillary nodes, and enhancing mass in left renal parenchyma with renal vein infiltration; lytic destruction of L4 and L5 vertebrae, left superior pubic ramus, and right ischium ​
• Biopsy of renal mass and bone biopsy confirmed metastatic clear cell RCC.

DISCUSSION QUESTION

1. Given time since completion of adjuvant therapy, do you consider this to be de novo metastatic disease or recurrence?

Beckermann: If the patient had instead received adjuvant pembrolizumab and then developed metastatic disease 1 year after completing that pembrolizumab, what would you recommend? This was a patient who had high disease burden, hematuria, and bone pain.

A few people chose cabozantinib [Cabometyx] as monotherapy because the patient had adjuvant pembrolizumab. Others are still choosing an IO/TKI regimen, either cabozantinib plus nivolumab [Opdivo] or pembrolizumab/axitinib. A couple people are looking at ipilimumab [Yervoy] plus nivolumab in the first-line setting. Given the time since completion of adjuvant therapy, would you consider this patient to have recurrent or de novo metastatic disease?

Raymond Lobins, DO: There are now at least 3 trials that have looked at IO after failing IO, and…they’re all negative. What is the thought process with adding IO after failure of an IO?

Thomas Oliver, MD: At least for me, [there is a] slightly different mechanism with the immune checkpoint inhibitor and you’re combining it with a TKI. I think you get some synergistic properties. In someone like this who was never cured, and this is recurrent aggressive disease, there is little downside, because after the first line [with] metastatic [disease], there are not the best [outcomes].

Gallagher: Plus, the duration of 1 year. I think it’s time based. It allows you to go back to immunotherapy.

Beckermann: We do have 2 great trials. [CONTACT-03; NCT04338269] looked at cabozantinib plus atezolizumab [Tecentriq] vs cabozantinib in the second-line setting. Patients had progression on IO/IO or IO/TKI. After some frontline IO-based regimen, they went straight into that randomization of either cabozantinib alone or cabozantinib/atezolizumab, and it was more toxic and did not prove beneficial over cabozantinib monotherapy.¹

Similarly, in TiNivo-2 [NCT04987203], patients didn’t have to have the IO as the most recent, but most of those patients had it within a certain number of months, not years.² The only question remaining after those negative trials in the metastatic setting is, is it a timing issue? In melanoma, we have data to say that the PD-1 receptor can be bound up to a year.^3,4 That time point is critical. If a patient has been away from IO and it’s a year later, is this new disease? I don’t think we know the answer. Some ongoing trials are looking at basing it on that timing decision.

Oliver: What are you doing [in this case]?

Beckermann: I’m using this 1-year cutoff until we have better data. I’ve had some patients with progression on [adjuvant] pembrolizumab. My more common scenario is, I’ve started pembrolizumab, and we’re at the first scan and there is progression, and then I’ll add something, because I don’t know that they’ve had enough time to respond to the pembrolizumab. If I’m 9 months into pembrolizumab and they’re actively on IO and there is progression, I tend to think it’s a failure of IO, and I tend to switch to a monotherapy. But when it’s a year after [completing pembrolizumab], it’s new disease. If it’s a healthy, fit patient, I try to give them the benefit of the doubt and do a dual agent in that setting. Hopefully we’ll have some data to guide us at some point.

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DISCLOSURES: Beckermann previously reported a consultant/advisor/speaker position for Aravive, Arcus, Alpine Bioscience, Aveo, Bristol Myers Squibb, Eisai, Exelixis, Merck, Nimbus, and Xencor.

REFERENCES

1. Pal SK, Albiges L, Tomczak P, et al. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2023;402(10397):185-195. doi:10.1016/S0140-6736(23)00922-4

2. Choueiri TK, Albiges L, Barthélémy P, et al. Tivozanib plus nivolumab versus tivozanib monotherapy in patients with renal cell carcinoma following an immune checkpoint inhibitor: results of the phase 3 TiNivo-2 study. Lancet. 2024;404(10460):1309-1320. doi:10.1016/S0140-6736(24)01758-6

3. Weber J, Del Vecchio M, Mandalá M, et al. Outcomes with postrecurrence systemic therapy following adjuvant checkpoint inhibitor treatment for resected melanoma in CheckMate 238. J Clin Oncol. 2024;42(31):3702-3712. doi:10.1200/JCO.23.01448

4. Weichenthal M, Ellebaek E, Mangana J, et al. Immune checkpoint inhibition in metastatic or non-resectable melanoma after failure of adjuvant anti-PD-1 treatment. A EUMelaReg real-world evidence study. Eur J Cancer. 2025;220:115339. doi:10.1016/j.ejca.2025.115339