How Cancer Teams Leverage Biology in Guiding First-Line Therapy for Clear Cell RCC

The biology of a patient and when treatment is initiated — rather than a patient’s risk stratification features — may best determine the appropriate frontline treatment for patients with clear cell renal cell carcinoma (RCC), an expert said.

Dr. Thomas Powels discussed this topic in a presentation during the 2023 Kidney Cancer Research Summit.

The [International Metastatic Renal Cell Carcinoma Database Consortium] classification is a fantastic prognostic indicator — good, intermediate and poor — and it works across broad subgroups of patients; but it doesn’t represent accurate biology,” Powels, director of Barts Cancer Center and professor of urology cancer at Barts Cancer Institute in London, England, said in a presentation during the 2023 Kidney Cancer Research Summit. “Within the biology of the good, the intermediate and the poorest disease, there will be responses to angiogenic therapy, to immune therapy, to both and (possibly) CTLA-4 as well. This is relatively important because if you think you’re selecting the biology of the patient for good-risk disease, that would be an inaccuracy.”

Powels added that classification is dynamic from the patient perspective, meaning that after patients under nephrectomy minimal residual disease is present, which may push patients into one classification over another. “With this biology of good, intermediate and poor (classifications), we know that those good-risk patients have more angiogenic signatures, but it’s not complete, and the poor patients have more immune type signatures. But again, that’s not complete,” Powels explained of understanding the full story of a patient’s biology and risk. “If you think that patients with good risk are all the same, that will be inaccurate, because just like cars, some cars go faster than others. And it depends on where the patients are in that journey, and how fast their cancers growing.”

Further, Powels pointed to how the timing of diagnosis is also relevant to the International Metastatic Renal Cell Carcinoma Database Consortium classification. “Those with aggressive biology, they go from good to intermediate to poor very quickly,” he said. “Then you’ve got an intermediate and a slow biology (where the tumor burden increases slower). In the slowest biology, patients may never get to poorest disease. But at snapshots in time, patients can be at different parts on the track.”

These International Metastatic Renal Cell Carcinoma Database Consortium and biology should be noted when considering available treatment options, but also depending on when treatment is initiated, clinicians should be aware that patients may shift International Metastatic Renal Cell Carcinoma Database Consortium classification based on response, Powels added. “I want you to think about it as a two-dimensional, not a one-dimensional picture of biology and time of presentation.”

Treatment Options for Patients With Clear Cell RCC

Data from the CheckMate 214 trial has demonstrated that treatment with the combination of Opdivo (nivolumab) and Yervoy (ipilimumab) has improved overall and progression-free survival (the time during and after treatment that a patient with cancer lives without disease worsening) for patients with intermediate/poor-risk disease versus Sutent (sunitinib). The median overall survival (the time when a patient with cancer is still alive) was 47 months with the immunotherapy combination (425 patients) versus 26.6 months with Sutent (422 patients). The 60-month overall survival rates were 43% and 31%, respectively. The median progression-free survival was 11.6 months in the investigative arm versus 8.3 months in the control arm. The 60-month progression-free survival rates were 31% and 11%, respectively.

“(These data are) transformative, (the combination) clearly beats (Sutent) out of the park,” Powels said.

Cross-trial comparisons require a bit more context, Powels said. For example, in terms of response, the conversations around response need to take into context that approximately 40% of patients’ response to Opdivo/Yervoy, he said. “If 75% of those (responses) are durable, that would then be 30% (overall). (The same could be said of) a VEGF TKI with a (durable) response rate of 60%. ... So, when you’re being told things about duration of response and some of these secondary or exploratory end points, I think it’s very important to put them in context, because we’re very liberal about how we throw the conversations around in this (ongoing) debate.”

In an example, Powels noted five-year follow-up data from the phase 3 KEYNOTE-426 trial of Keytruda (pembrolizumab) plus Inlyta (axitinib) versus Sutent demonstrate how VEGF/PD-1 dual inhibition has good initial control of disease, which is important for some patients, whereas the Opdivo/Yervoy data may look less desirable for those with good risk disease, but over time, the efficacy does appear to catch up in terms of response and progression-free survival.

For KEYNOTE-426 specifically, the median overall survival was 47.2 months with the combination (432 patients) versus 40.8 months in the control arm (429 patients). The 60-month overall survival rate was 41.9% versus 37.1%, respectively. For progression-free survival, the median in the Keytruda/Inlyta arm was 15.7 months versus 11.1 months in the Sutent arm, with 60-month progression-free survival rates of 18.3% and 7.3%, respectively.

Adding to this landscape are data from the final prespecified analysis of the phase 3 CLEAR trial. In the trial, patients with clear cell RCC were randomly assigned to the investigative arm of Lenvima (lenvatinib) plus Keytruda or Afinitor (everolimus) or the control arm of Sutent. The median overall survival was 53.7 months with the combination of Lenvima plus Keytruda (355 patients) versus 54.3 months with Sutent (357 patients). The 36-month overall survival rate was 66.4% versus 60.2%, respectively.

A continued progression-free survival benefit was observed with the combination of Lenvima and Keytruda at 23.9 months versus 9.2 months with Sutent. The 36-month progression-free survival rates were 37.3% versus 17.6%, respectively.

Finally, according to longer-term data from the phase 3 CheckMate 9ER trial, the median overall survival with the investigational regimen of Opdivo and Cabometyx (cabozantinib) was 49.5 months versus 35.5 months with Sutent.

“I think this issue around comparing the trials, which we like to do … and I think we’re creating inaccuracies in some of the things we say, and I’m including myself with this debate,” Powels said. “Essentially, we have four good options, all of which have beaten (Sutent) with more similarities than differences. The best duration of these therapies is undefined. CTLA-4 is likely to help but we haven’t defined exactly how much it helps yet. Good risk disease is complicated. We need to focus on that the trials are hard to do they take longer and therefore (we) aren’t doing them. But I worry those patients may get left behind.”

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