Several renal cell carcinoma (RCC) readouts from the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting raised questions about how toxicity, quality of life, and immature survival data should factor into treatment selection. CancerNetwork® spoke with María Teresa Bourlon, MD, MSc, FASCO, head of the Urologic Oncology Clinic at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in Mexico City, Mexico, about 3 of these studies: the phase 2 LenCabo trial (NCT05012371) of lenvatinib (Lenvima) plus everolimus (Afinitor) vs cabozantinib (Cabometyx) in metastatic clear cell RCC, the phase 3 RAMPART trial (NCT03288532)of adjuvant durvalumab (Imfinzi) with or without tremelimumab (Imjudo) vs active monitoring in resected primary RCC, and the phase 2 RADICAL trial (NCT04071223) of cabozantinib with or without radium-223 in RCC with bone metastases.1-3
CancerNetwork: The LenCabo findings showed that lenvatinib plus everolimus was also associated with significantly greater reductions in body mass index (BMI), skeletal muscle mass index, and subcutaneous adiposity at 4 months. How should that catabolic signal factor into regimen selection, particularly for older or frailer patients?
Bourlon: This is important data. Whenever we’re prescribing a tyrosine kinase inhibitor [TKI] in any line of treatment for RCC, we’re concerned about its catabolic effect, especially reducing muscle mass and the strength of the patient. This [LenCabo] data—a combination therapy of lenvatinib plus everolimus vs cabozantinib—speaks about what to expect for the patient. These results tell us that we could expect patients to become frailer and to lose their muscle mass and strength.
This is a real concern when we have an older patient from a geriatric population, a frail patient, or a patient who has lost a lot of weight. This is a significant toxicity that may impact outcomes, may preclude patients from receiving full dose, and may even impact their quality of life [QOL] because they’re not going to be able to do their daily activities. We’re lacking better measurements in clinic to really see the impact of these medications on musculoskeletal toxicity, but this abstract is really informative to help us rethink whether we need to give this combination to patients who are frail, older, or who have lost a lot of muscle mass.
The FKSI-DRS [Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease-Related Symptoms] QOL comparison at day 60 was inconclusive, with a non-significant OR of 0.51, based on only 38 of 86 patients completing both assessments. How much weight should clinicians put on that finding given the incomplete data capture, and what would more complete patient-reported outcome collection need to look like in a future trial?
This is a limitation not only for this study, but for every kidney cancer study. Whichever tool we use to measure [QOL], we know it isn’t perfect; we can improve these tools, but it’s still hard to have a good instrument. On top of that, in clinical trials we rarely achieve 100% response from patients, and it’s particularly notable in this trial that less than 50% of patients answered the [QOL] questionnaire. That’s a limitation that also limits how we can interpret the data presented.
Having a real difference in [QOL] would be very meaningful. If the combination had demonstrated better [QOL], we’d all lean more toward prescribing it, but knowing the result was inconclusive, we really can’t tell whether there’s a difference between lenvatinib/everolimus and cabozantinib. We don’t have the tools to tell a patient which drug will be better for their [QOL]. We don’t yet know whether we’re measuring what we want to measure in terms of [QOL] for our patients. For me, this finding doesn’t tip the balance toward one drug or the other at this point.
In the RAMPART trial, the durvalumab monotherapy arm showed a 26% relative reduction in disease recurrence or death, falling short of the trial’s prespecified significance threshold, while durvalumab plus tremelimumab did meet it. How should clinicians interpret this distinction, and does it change how you’d counsel a patient toward single-agent vs combination adjuvant immunotherapy?
[That’s] a complex scenario nowadays. After radical nephrectomy, for patients at high risk of recurrence who receive adjuvant therapy, we already have a standard of care, pembrolizumab [Keytruda], which has demonstrated an overall survival [OS] benefit. Any combination or monotherapy needs to prove an OS benefit of its own; until it does, we’re all going to be hesitant to prescribe it because we already have an alternative that improves OS. At this point, neither the combination nor the monotherapy is going to replace pembrolizumab as the standard of care. We need more follow-up to see whether either regimen demonstrates not just disease-free survival [DFS] but OS. The bar is higher now. We need to see OS before we call this a new standard of care.
How will durvalumab and tremelimumab fit into the current adjuvant treatment landscape, and what would you want to see from the still-pending OS and quality-of-life data before adopting it into practice?
We do want an OS benefit, since pembrolizumab already has one. For combination therapy, we have studies of ipilimumab [Yervoy]/nivolumab [Opdivo] and durvalumab/tremelimumab, and we’ve now also seen the pembrolizumab plus belzutifan [Welireg] study with improved DFS, but we all want to see an OS benefit. We’re aware that combination therapy might be more toxic and lead to an increase in adverse events. [QOL] data and toxicity are going to be key for clinicians deciding between monotherapy and combination therapy in the adjuvant setting, on top of OS, so this data needs to mature.
We need updated analyses, and we need to be very careful in assessing toxicity because bad toxicity can lead to bad [QOL]. We need to remember that many of these patients can already be cured, so we don’t want to give bad toxicity to a long-term survivor. I don’t consider either of these regimens standard of care yet, while we do have a standard of care that improves OS, which is pembrolizumab monotherapy.
The RADICAL trial closed early due to futility. How do you reconcile the negative primary end point, symptomatic skeletal event-free survival, with the OS separation observed? Which end point do you think best reflects clinical benefit in this population?
This is very hard because our primary end point was negative. Whether there’s really a difference in OS, I’m not sure we have enough power to say at this moment. There could be many contributing factors, like sequencing of drugs and what patients received in second, third, or further lines of therapy. It’s important to remember that this trial closed early due to futility, so it’s going to remain inconclusive; it didn’t recruit the predetermined number of patients or events needed to interpret other end points. We need to understand that whenever a trial closes due to futility, you’re no longer able to reliably address its other end points.
Adding radium-223 to cabozantinib increased grade 3 or higher treatment-related AEs without improving symptomatic skeletal event-free survival. From a multidisciplinary perspective, how should medical and radiation oncologists weigh that added toxicity against the observed survival trend when counseling patients with symptomatic, bone-metastatic RCC?
At this point, we need to understand that this combination won’t get approval. We all understand the rationale for testing it, since kidney cancer bone metastases can be very symptomatic, and we’re glad to see a drug tested that could decrease skeletal-related events. Nevertheless, the drug wasn’t able to do this, and the trial closed due to futility.
If we’re seeing higher grade 3 toxicity, that means we’re deteriorating the patient’s [QOL], so for a trial that closed early, [the findings] can’t be conclusive about other outcomes such as [OS]. I’d be very cautious about interpreting this combination as improving [OS]. I’d rather view this as a trial with a reasonable hypothesis about a potential synergy between the drugs, designed to decrease skeletal-related events, that closed early due to futility. It’s very hard to interpret any data from this study beyond the fact that it didn’t improve its primary end point.
References
- Moura J, Chahoud J, Skelton WP IV, et al. Body composition and quality of life (QOL) with lenvatinib + everolimus (len + eve) vs cabozantinib (cabo) in metastatic clear cell renal cell carcinoma (ccRCC) after PD-1 inhibitor progression: results from the randomized phase II LenCabo trial. J Clin Oncol. 2026;44(suppl 16):4538. doi:10.1200/JCO.2026.44.16_suppl.4538
- Larkin JMG, Powles T, Frangou E, et al. Durvalumab monotherapy versus active monitoring for resected primary renal cell carcinoma in RAMPART: an international, phase 3, randomized controlled trial. J Clin Oncol. 2026;44(suppl 17):LBA4511. doi:10.1200/JCO.2026.44.17_suppl.LBA4511
- McKay RR, Atherton P, Ballman KV, et al. A phase 2 randomized trial of radium-223 dichloride and cabozantinib in patients (pts) with renal cell carcinoma (RCC) with bone metastases (BM): RADICAL (Alliance A031801). J Clin Oncol. 2026;44(suppl 16):4500. doi:10.1200/JCO.2026.44.16_suppl.4500
