Advancements With Combination Therapies in RCC Usher in New Questions

As combination therapies have changed the management of clear cell renal cell carcinoma (RCC) over the years, investigators are parsing out which combinations are the most effective and safe keeping histology in mind and looking towards modern approaches for refractory disease, according to Benjamin L. Maughan, MD, PharmD.

Findings from the final overall survival (OS) analysis of the phase 3 JAVELIN Renal 101 trial (NCT02684006) presented at the 2024 ASCO Annual Meeting represented the longest follow-up data of an immune checkpoint inhibitor and TKI combination therapy in a phase 3 trial. Data demonstrated that patients with advanced RCC treated with avelumab (Bavencio) plus axitinib (Inlyta; n = 442) in the frontline experienced a median OS of 44.8 months (95% CI, 39.7-51.1) compared with 38.9 months (95% CI, 31.4-45.2) among patients given sunitinib (Sutent; n = 444; HR, 0.88; 95% CI, 0.749-1.039); 1-sided P = .0669). The median progression-free survival (PFS) was 13.9 months (95% CI, 11.1-16.6) vs 8.5 months (95% CI, 8.2-9.7), respectively (HR, 0.66; 95% CI, 0.566-0.769; 1-sided P < .0001).

“For clear cell kidney cancer, now that we’re routinely using combination therapies up front and all those combinations include some component of immunotherapy, we’re starting to wrestle with the challenge of what to do when a patient’s cancer has become resistant to immunotherapy. [With my institution’s] tumor board where we are incorporating a lot of clinical trials, we’re trying to identify novel approaches to reengage or reignite the immune system in that IO-refractory tumor environment,” Maughan explained.

In an interview with OncLive®, Maughan, an assistant professor in the Division of Medical Oncology at Huntsman Cancer Institute in Salt Lake City, Utah, discussed the implications of immuno-oncology (IO) and TKI agent combinations in clear cell and non–clear cell RCC.

OncLive: How has the treatment and management of clear cell RCC changed and what do you attribute those changes to?

Maughan: One significant change regarding clear cell kidney cancer over the past 5 years or so has been the understanding that certain combinations significantly improve OS as well as a number of key end points such as PFS and quality of life for patients compared with single-agent sequential therapy. There are many combinations that can be selected from, but combinations are a much more effective way to approach [treatment for this patient population]. Several abstracts presented at ASCO 2024 continue to better help [us] understand this [as well, including] long-term follow up [data] of the JAVELIN Renal 101 study [and] long-term follow-up understanding the length of survival and PFS among different cohorts in the phase 3 CheckMate 9ER study [NCT03141177].

Across multiple phase 3 trials, specific combinations [have] shown significant improvements in OS whether it’s IO/IO [combinations such as] nivolumab [Opdivo] plus ipilimumab [Yervoy] or certain TKI/IO combinations such as lenvatinib [Lenvima] plus pembrolizumab [Keytruda], cabozantinib [Cabometyx] plus nivolumab, or axitinib [Inlyta] plus pembrolizumab. That’s one of the biggest advances in clear cell kidney cancer over the past 5 years, especially in terms of first-line treatments.

What changes in the management of non–clear cell RCC have been notable?

With non–clear cell kidney cancer, the biggest advance that we’ve seen over the past 5 years and that continues to be true even with data releases at ASCO this year, [is a] paradigm shift from bunching all variant or non–clear cell kidney cancers together to branching out; [we are] starting to research them individually both [with] laboratory studies to better understand the specific disease biology of each of these entities as well as now with clinical trials and other forms of clinical research in various disease-specific histologies.

For instance, an abstract presented at ASCO looked at 99 patients in a multi-institutional retrospective analysis for chromophobe kidney cancer; [it examined] outcomes of first-line treatment [with] TKI monotherapy vs combination therapy [with either a] TKI/IO or IO/IO combination. This is the biggest change that we’re seeing with the variant or non–clear cell histologies—we’re starting to appreciate each is a unique disease and needs unique treatments and has unique outcomes.

How have these changes affected your approach to treatment planning with patients and tumor board discussions with other multidisciplinary specialties?

[These advances have] tremendously changed that. With non–clear cell histologies, it is very important to have this multidisciplinary tumor board because pathology is particularly important. Are we truly understanding what the histology is and trying to do the best that we can to not lump inordinate groups of patients in this unclassified bucket? Are we trying to understand [if] we can better refine their disease based on these molecular characteristics? Another important aspect of tumor boards particularly for a lot of these non–clear cell histologies, because we do have fewer treatments that are clearly effective for them, [are] focal treatments to try and debulk [which] oftentimes can be a very important strategy to try and improve PFS and hopefully OS.

Are there any clinical trials in the IO-refractory setting for clear cell disease that you would like to highlight?

Several interesting IO-refractory studies are ongoing, and some were presented at ASCO this year, including [trials] with interesting cellular therapies. Novel approaches are looking at various CAR T-cell or CAR-NK engineered products targeting PSMA or CD70 [for example]. That’s an interesting approach that has a lot of promise for addressing [needs in] this IO-refractory population.

There’s a bit of ongoing work looking at trying to target alternative checkpoints as well. This hasn’t proven to be necessarily a huge blockbuster so far, but there’s initial promising signals that may be useful for some patients [with] targeting alternative checkpoints. Some of the biomarker work has shown that one of the mechanisms of resistance to PD-1 based therapies is upregulation or downregulation of alternative checkpoints whether those are coinhibitory or costimulatory checkpoints, respectively. That may be an effective way to deal with this immune resistant environment. None of the studies at ASCO are at the point where they are practice changing, but from a research perspective they’re very practicing informing in terms of how we develop and think about the next generation of clinical trials.

Reference

Motzer RJ, Penkov K, Uemura H, et al. Avelumab + axitinib vs sunitinib in patients (pts) with advanced renal cell carcinoma (aRCC): final overall survival (OS) analysis from the JAVELIN Renal 101 phase 3 trial. J Clin Oncol. 2024;42(suppl 16):4508. doi:10.1200/JCO.2024.42.16_suppl.4508