Leveraging Biology to Guide First-Line Treatment of Clear Cell RCC


Determining the appropriate front-line treatment pathway for patients with clear cell renal cell carcinoma may not always align with risk stratification features.

Thomas Powles, MD

Thomas Powles, MD

Determining the appropriate front-line treatment pathway for patients with clear cell renal cell carcinoma (RCC) may not always align with risk stratification features, according to Thomas Powles, MD. Rather, the biology of the patient and treatment initiation time points may better guide clinical decisions.1

The [International Metastatic Renal Cell Carcinoma Database Consortium] IMDC 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,” Powles, 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.

Powles added that classification is dynamic from the patient perspective, meaning that after patients under nephrectomy minimal residual disease (MRD) 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,” Powles 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 cancer's growing.”

Further, Powles pointed to how the timing of diagnosis is also relevant to the IMDC 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 IMDC 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 IMDC classification based on response, Powles added. “I want you to think about it as a 2-dimensional not a 1-dimensional picture of biology and time of presentation.”

Treatment Options for Patients With Clear Cell RCC

Data from the CheckMate 214 (NCT0223149) trial have demonstrated that treatment with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) has improved overall and progression-free survival (PFS) for patients with intermediate/poor-risk disease vs sunitinib (Sutent). The median overall survival (OS) was 47.0 months (95% CI, 35.4-57.4) with the immunotherapy combination (n = 425) vs 26.6 months (95% CI, 22.1-33.5) with sunitinib (n = 422; HR, 0.68; 95% CI, 0.58-0.81; P = .0001).2 The 60-month OS rates were 43% and 31%, respectively. The median PFS was 11.6 months (95% CI, 8.4-16.5) in the investigative arm vs 8.3 months (95% CI, 7.0-10.4) in the control arm (HR, 0.73; 95% CI, 0.61-0.87; P = .0004). The 60-month PFS rates were 31% and 11%, respectively.

“[These data are] transformative, [the combination] clearly beats sunitinib out of the park,” Powles said. “The survival curve is particularly impressive. There have been concerns around the PFS curve and the plateau. The plateau is real, but not all patients have made it to that plateau. Some patients have been censored prior to that. And that’s what the debate is around. This is not an inaccurate curve. It’s just not representation of all the patients. It is impressive, that there is a durable remission associated with the option.”

Cross-trial comparisons require a bit more context, Powles said. For example, in terms of response, the conversations around response need to take into context that approximately 40% of patients’ response to nivolumab/ipilimumab, 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, Powles noted 5-year follow-up data from the phase 3 KEYNOTE-426 trial (NCT02853331) of pembrolizumab (Keytruda) plus axitinib (Inlyta) vs sunitinib demonstrate how VEGF/PD-1 dual inhibition has good initial control of disease, which is important for some patients, whereas the nivolumab/ipilimumab 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 PFS.

For KEYNOTE-426 specifically, the median OS was 47.2 months (95% CI, 43.6-54.8) with the combination (n = 432) vs 40.8 months (95% CI, 34.3-47.5) in the control arm (n = 429; HR, 0.84; 95% CI, 0.71-0.99). The 60-month OS rate was 41.9% vs 37.1%, respectively. For PFS, the median in the pembrolizumab/axitinib arm was 15.7 months (95% CI, 13.6-20.2) vs 11.1 months (95% CI, 8.9-12.6) in the sunitinib arm (HR, 0.69; 95% CI, 0.59-0.81), with 60-month PFS rates of 18.3% and 7.3%, respectively.3

Adding to this landscape are data from the final prespecified analysis of the phase 3 CLEAR trial (NCT02811861).4 In the trial patients with clear cell RCC were randomly assigned to the investigative arm of lenvatinib (Lenvima) plus pembrolizumab or everolimus (Afinitor) or the control arm of sunitinib. The median OS was 53.7 months (95% CI, 48.7-not estimable [NE]) with the combination of lenvatinib plus pembrolizumab (n = 355) vs 54.3 months (95% CI, 40.9-NE) with sunitinib (n = 357; HR, 0.79; 95% CI, 0.63-0.99; nominal P = .0424). The 36-month OS rate was 66.4% vs 60.2%, respectively. However, among those with favorable-risk disease, the HR between the treatments was 0.94 (95% CI, 0.58-1.52) compared with 0.74 (95% CI, 0.57-0.96) for those with intermediate/poor disease.

A continued PFS benefit was observed with the combination of lenvatinib and pembrolizumab at 23.9 months (95% CI, 20.8-27.7) vs 9.2 months (95% CI, 6.0-11.0) with sunitinib (HR, 0.47; 95% CI, 0.38-0.57; P < .0001). The 36-month PFS rates were 37.3% vs 17.6%, respectively.4

Finally, according to longer-term data from the phase 3 CheckMate 9ER trial (NCT03141177), the median OS with the investigational regimen of nivolumab and cabozantinib (Cabometyx) was 49.5 months vs 35.5 months with sunitinib (HR 0.70; 95% CI, 0.56-0.87).5

“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,” Powles said. “Essentially, we have 4 good options, all of which have beaten sunitinib 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.”


  1. Powles T. Front line systemic therapy strategies. Presented at: 2023 Kidney Cancer Research Summit; July 13-14, 2023; Boston, MA.
  2. Motzer RJ, McDermott DF, Escudier B, et al. Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma. Cancer. 2022;128(11):2085-2097. doi:10.1002/cncr.34180
  3. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab + axitinib versus sunitinib as first-line therapy for advanced clear cell RCC: 5-year analysis of KEYNOTE-426. J Clin Oncol. 2023;41(suppl 17):LBA4501. doi:10.1200/JCO.2023.41.17_suppl.LBA4501
  4. Motzer RJ, Porta C, Eto M, et al. Final prespecified overall survival (OS) analysis of CLEAR: 4-year follow-up of lenvatinib plus pembrolizumab (L+P) vs sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol. 2023;41(suppl 16):4501. doi:10.1200/JCO.2023.41.16_suppl.4502
  5. Burotto M, Powels T, Escudier B, et al. Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial. J Clin Oncol. 2023;41(suppl 6):603. doi:10.1200/JCO.2023.41.6_suppl.603
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