Discovering Treatment Biomarkers Remains an Important Goal in RCC

Daniel M. Geynisman, MD

Associate Professor

Department of Hematology/Oncology

Vice Chair, Quality Improvement Program

Fox Chase Cancer Center

Philadelphia, PA

Recent years have brought multiple new therapeutic strategies to patients with renal cell carcinoma (RCC) across settings, with new research aimed at deciphering which treatments work best in distinct patient subgroups.

During Kidney Cancer Awareness Month, CancerNetwork^® sat down with Daniel M. Geynisman, MD, associate professor in the Department of Hematology/Oncology and vice chair of the Quality Improvement Program at Fox Chase Cancer Center in Philadelphia, Pennsylvania, who spoke about research in RCC and trials he’s eager to see the results of.

Geynisman offered his take on the treatment paradigm following important updates presented at the 2022 Genitourinary Cancers Symposium. He discussed adjuvant therapy in high-risk resected disease, finding treatment biomarkers for metastatic tumors, and ongoing clinical trials that clinicians should be aware of.

CancerNetwork^®: What emerging research in RCC do you think has the greatest potential for clinical impact?

Geynisman: One of the practice changing results that we’ve seen since the ASCO 2021 [2021 American Society of Clinical Oncology Annual Meeting] is adjuvant immunotherapy for high-risk kidney cancer, with [the use of] pembrolizumab [Ketruda].¹ Given the data presented at ASCO 2021 and the subsequent New England Journal of Medicine publication, pembrolizumab was FDA approved in the adjuvant setting and the data was updated at the [2022 Genitourinary Cancers Symposium].^2-4 This is the first immunotherapy approved in the adjuvant space in RCC, and it led to not just statistically significant, but clinically meaningful, disease-free survival benefit. That has changed the therapeutic landscape and is going to continue to impact the landscape of treatment because it effects not just the adjuvant setting, but then the frontline setting for someone who’s already received adjuvant immunotherapy and unfortunately has disease recurrence. Importantly, we are still awaiting the overall survival data [and that] may take some time. We’re also still awaiting multiple other adjuvant trials to read out before we make final conclusions about this adjuvant immunotherapy approach. However, this is now an important option for patients with high-risk kidney cancer after surgery and is an important step forward for patients.

The holy grail has been and is going to continue to be biomarker-driven approaches in kidney cancer—finding the right patient for the right combination. As an example, I would love to know that the patient sitting in front of me is going to respond to the pure immunotherapy combination of ipilimumab [Yervoy] and nivolumab [Opdivo], that I don’t have to give them TKIs [tyrosine kinase inhibitors], and that they’re not going to need any further treatment 5 years out and be one of the patients on the ‘tail-of-the-curve’ that we often talk about. Unfortunately, I don’t have that ability right now. There’s no test I can run. Thus, most of my decisions are largely clinically based and although there are some associations one can find from baseline clinical factors and response to therapy, they’re not very robust. That’s what’s missing in kidney cancer. It is the predictive biomarkers to help us select the right therapy, both in the frontline and later lines of therapy. There’s much work going on in that, but none of it is quite ready for primetime. There is great work being done on this topic—for example, looking at various clusters of kidney cancer, whether they are driven by and angiogenic pathways or immune pathways or neither, and placing patients as part of a clinical trial on treatment based on those clusters. That’s something we should all support and will hopefully move the field forward.

Are there any trials you are eager to see the results of?

The trial that would read out the soonest and that everyone is quite excited to see [the results of] is the triplet of ipilimumab, nivolumab, and cabozantinib [Cabometyx] versus ipilimumab/nivolumab [COSMIC-313; NCT03937219]. It’ll be the first modern trial where the comparator arm is a standard of care that we currently use. It’ll try to combine the best IO [immunotherapy] regimen plus TKI versus the IO regimen. What we would like to see is what that complete response rate is, what the toxicity is going to be like, and what the progression-free survival is going to be. We may not have overall survival results right away, but that’s the one trial that I’m most excited about. I think [it has the greatest] potential to change that landscape for frontline disease.

Are there any trials that clinicians treating patients with RCC should be aware of for recruitment?

The phase 3 trial of everolimus [Afinitor] plus belzutifan [Welireg] did complete accrual [NCT04195750], but that’s an important trial that we’re going to wait [for the results of] because that will hopefully bring a completely novel drug to all patients with clear cell kidney cancer. Now, the drug is approved just for patients with VHL [von Hippel–Lindau disease].⁵

A trial that is about to open is a new adjuvant trial of pembrolizumab plus belzutifan versus pembrolizumab [NCT05239728]. Both arms will be getting pembrolizumab, and I think that is probably the next important question in the adjuvant space. Belzutifan is relatively well tolerated—usually better than a TKI—so it potentially takes away the problem of adjuvant TKI which patients really don’t like to [take] for a year. That’ll be an important trial, and then there are other trials like the PDIGREE trial [NCT03793166] that is ongoing with ipilimumab/nivolumab, and then separating patients out into their next line of therapy based on their response. That will also be an important trial to answer some questions regarding how you sequence treatment and that trial is still open in accruing patients, so I think that’s something important to look out for and it’s open throughout the country.

Is there anything else that we didn’t cover that you’d like to talk about?

We [did not] mentioned non–clear cell RCC. There’s a high unmet need for developing therapies for non–clear cell RCC. All the trials that people usually speak about are really designed for clear cell RCC, there have been a number of trials ongoing looking at IO/TKI combinations for non–clear cell RCC, so we eagerly await those results. I think it is important to look around and see if there’s a trial open in your area if you see a patient with non–clear cell disease because those [tumors] are quite biologically distinct. There are many different non–clear cell subtypes, and that’s [an area in which] we still have quite a bit of work to do.

References

1. Choueiri TK, Tomczak P, Park SH, et al. Pembrolizumab vs placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: randomized, double-blind, phase 3 KEYNOTE-564 study. J Clin Oncol. 2021;39(suppl 15):LBA5. doi:10.1200/JCO.2021.39.15_suppl.LBA5
2. Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385(8):683-694. doi:10.1056/NEJMoa2106391
3. FDA approves pembrolizumab for adjuvant treatment of renal cell carcinoma. News Release. FDA. November 17, 2021. Accessed March 4, 2022. https://bit.ly/3hIkMTb
4. Choueiri TK, Tomczak P, Park SH, et al. Pembrolizumab as post nephrectomy adjuvant therapy for patients with renal cell carcinoma: Results from 30-month follow-up of KEYNOTE-564. J Clin Oncol. 2022;40(suppl 6):290. doi:10.1200/JCO.2022.40.6_suppl.290
5. FDA approves belzutifan for cancers associated with von Hippel-Lindau disease. FDA. August 13, 2021. Accessed March 8, 2022. https://bit.ly/3vMgRwV

For additional interviews with leaders in the treatment of pancreatic cancer, see other CancerNetwork® interviews conducted for pancreatic cancer awareness month:

• RCC Paradigm Continues Moving Forward With New Combination Regimens on the Horizon
• Examining Frontline Immune Checkpoint Inhibitor Combinations in Advanced RCC With Laurence Albigès, MD, PhD
• Activity in Ongoing Trials Suggest New Agents Are on the Horizon for RCC