Scratching the Surface in Managing Advanced RCC

Matthew T. Campbell, MD, MS

Associate Professor and Associate Medical Director,

Department of Genitourinary Medical Oncology

The University of Texas MD Anderson Cancer Center

As part of an Around the Practice program hosted by
 CancerNetwork, Campbell spoke about recent advancements
in therapeutic strategies for patients with advanced renal cell
carcinoma (RCC).

Campbell highlighted the use of immunotherapy agents as a prominent treatment strategy in the field and discussed how this standard may evolve following updated results presented at the 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium. Regarding other therapeutic considerations, he spoke about optimizing treatment selections based on the use of molecular profiling and agents that most benefit patient quality of life (QOL).

Looking ahead, Campbell said he hopes to see advancements in neoadjuvant therapy as well as biomarkers such as circulating tumor DNA (ctDNA) to predict disease recurrence more accurately. Overall, he stated, practices have only “begun to scratch the surface” of therapy for patients with advanced RCC.

Q / What is the current standard of care (SOC) in advanced RCC?

Campbell / The current SOC for the vast majority of patients is an immunotherapy [IO] combination. We will often use nivolumab [Opdivo] or ipilimumab [Yervoy] for patients we think can tolerate therapy and are at a lower risk of rapid, progressive disease. We’ll use an IO–tyrosine kinase inhibitor [TKI] strategy for patients who have a high risk of rapidly progressive disease.

Q / Looking at the presentations from the 2024 ASCO GU Cancers Symposium, do you believe any results have the potential to impact the SOC?

Campbell / I do. Pembrolizumab [Keytruda] having an overall survival advantage in the phase 3 KEYNOTE-564 trial [NCT03142334] is a huge deal in the adjuvant space.¹ That is a transformative study. It’s one that has potentially changed the landscape of frontline therapy because if more patients are going to receive adjuvant immunotherapy, we’re going to have to figure out what to do with patients in the frontline setting who have progressed. That’s a trial that has transformed us.

Q / Before preparing a treatment plan, do you utilize molecular profiling or genetic testing?

Campbell /In some patients, we will use molecular profiling. As of today, outside of World Health Organization classifiers, it doesn’t have a role in terms of us picking frontline therapy. We know that patients with BAP1 mutations have a negative prognostic marker, but it’s not predictive, so what do we use in pathology? We use sarcomatoid dedifferentiation. If patients have this on their pathology, we will often select nivolumab plus ipilimumab [as a treatment] because response rates are approximately 60%, and complete response rates are approximately 20%. We know that those patients are less responsive to TKI-based treatment.

Q / How are you incorporating patient preferences and QOL considerations into your treatment decision-making for patients with advanced RCC?

Campbell / QOL is hugely important for patients, and this is something that I go to great lengths in discussing. Nivolumab and ipilimumab have improved QOL compared with sunitinib [Sutent],² as did cabozantinib [Cabometyx] plus nivolumab vs sunitinib.³ This is important. With axitinib [Inlyta] plus pembrolizumab and lenvatinib [Lenvima] plus pembrolizumab, QOL was about the same as [with] sunitinib, which was not great.^4,5 When we have this [decision-making] conversation, [QOL] is a big part of it. Part of it’s because the cabozantinib dose is lower and tends to be a bit of an easier start for patients, especially those who are frail.

Q / Looking toward the future, how do you hope to see the RCC field evolve?

Campbell / I hope that neoadjuvant therapy becomes an option. It’d be wonderful if we could cure more patients in the localized setting and identify patients who are at the highest risk of progression. [Another hope is] developing better biomarkers, including ctDNA, to pick out patients who are at a higher risk of disease recurrence or have active disease. Understanding how molecular profiling can better predict the outcomes of different therapies is going to be important. We’ve just begun to scratch the surface in terms of therapy. The development of chimeric antigen receptor [CAR] technology and novel immunotherapy approaches is going to lead to a very bright future over the next decade and beyond.

References

1. Choueiri TK, Tomczak P, Park SH, et al. Overall survival results from the phase 3 KEYNOTE-564 study of adjuvant pembrolizumab versus placebo for the treatment of clear cell renal cell carcinoma (ccRCC).J Clin Oncol.2024,42(suppl 4):LBA359. doi:10.1200/JCO.2024.42.4_suppl.LBA359
2. Motzer RJ, Tannir NM, McDermott DF, et al: CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126
3. Cella D, Motzer RJ, Suarez C, et al. Patient-reported outcomes with first-line nivolumab plus cabozantinib versus sunitinib in patients with advanced renal cell carcinoma treated in CheckMate 9ER: an open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(2):292-303. doi:10.1016/S1470-2045(21)00693-8
4. Bedke J, Rini BI, Plimack ER, et al. Health-related quality of life analysis from KEYNOTE-426: pembrolizumab plus axitinib versus sunitinib for advanced renal cell carcinoma. Eur Urol. 2022;82(4):427-439. doi:10.1016/j.eururo.2022.06.009
5. Motzer R, Porta C, Alekseev B, et al. Health-related quality-of-life outcomes in patients with advanced renal cell carcinoma treated with lenvatinib plus pembrolizumab or everolimus versus sunitinib (CLEAR): a randomised, phase 3 study. Lancet Oncol. 2022;23(6):768-780. doi:10.1016/S1470-2045(22)00212-1