Braun Highlights Advances in RCC Treatment Paradigm, Looks Towards Future

Patients with renal cell carcinoma (RCC) have gained more and more effective treatment options over time, but there are still areas of unmet need in which these therapies can be used as the building blocks of additional effective regimens, according to David A. Braun, MD, PhD.

“Over the past number of years, we’ve seen the emergence of the immune checkpoint era, both in the refractory setting, in the frontline metastatic setting, and now even in the adjuvant setting. This has become the backbone for modern therapies today,” Braun said.

In April 2024, updated overall survival (OS) findings from the phase 3 KEYNOTE-564 trial (NCT03142334) examining pembrolizumab (Keytruda) monotherapy for the adjuvant treatment of patients with RCC following nephrectomy were published in the New England Journal of Medicine following their presentation at the 2024 Genitourinary Cancers Symposium (ASCO GU). At a median follow-up of 57.2 months, the 48-month OS rates were 91.2% vs 86.0% among patients who received pembrolizumab (n = 496) vs placebo (n = 498), respectively (HR, 0.62; 95% CI, 0.44-0.87; P = .005). Previous findings from the study supported the November 2021 FDA approval of pembrolizumab for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.^1,2

In an interview with OncLive, Braun, assistant professor, medicine (medical oncology), Louis Goodman and Alfred Gilman Yale Scholar, member, Center of Molecular and Cellular Oncology, at Yale Cancer Center in New Haven, Connecticut, discussed the evolution of the treatment landscape of RCC and provided a snapshot of his presentation on the future landscape of immunotherapy he gave during the 2024 ASCO Annual Meeting.

OncLive: Where does the modern-day treatment paradigm of RCC stand?

Braun:We’ve seen an evolution in the treatment of [patients with] kidney cancer over the past number of years in a very positive way. Over 20 years ago, immunotherapy was a cornerstone when there weren’t many other therapies—cytotoxic chemotherapy didn’t have a big effect. But that was largely cytokine-based therapy, and although there were some patients who responded incredibly well that was a very small number.

Then we saw the rise of the anti-angiogenic era around 2005 to 2006; that was a landmark moment for kidney cancer, but it didn't lead to many durable [responses] or long-term survival. These were transient responses that were meaningful, but nothing that was truly long lived, at least not for the majority of patients.

In first-line metastatic kidney cancer, particularly clear cell disease which is 75% of kidney cancers and where we have the strongest data by far in terms of how we think about therapies, immunotherapy should be a backbone of systemic therapy for most, if not all, patients, unless there are specific reasons [for it] not to [be]. There’s lots of discussion about what that means, do you use a pure immunotherapy approach, such as with nivolumab [Opdivo] and ipilimumab [Yervoy], or 1 anti–PD-1 drug and a TKI.

Those [approaches] have never been compared head to head and there’s probably a role for each. We’ve seen with the caution about cross-trial comparisons that the pure immunotherapy regimen can have some durable responses when there is a response. We’ve seen long-term follow-up from studies such as [the phase 3] CheckMate 214 trial [NCT02231749] where the [DOR] goes on for many of those patients, but the upfront response rate is quite a bit lower than the that of an immunotherapy plus a TKI. That’s the tradeoff; those immunotherapy plus TKI regimens can have incredibly high response rates, even north of 70%, but those responses are often transient, with a median DOR of approximately 2 years.

Sometimes you need to obtain an upfront response when it’s critical to get disease control and shrinkage. Those are situations where I tend to favor an immunotherapy [plus a] TKI. Then there are situations where you have a bit of time and you think more about the long term and in those cases, I tend to favor more immunotherapy plus immunotherapy-based regimens.

What do you make of the positive results from the KEYNOTE-564 trial in the adjuvant setting?

For decades, the adjuvant setting has been incredibly difficult for kidney cancer with the series of trial failures that unfortunately have not led to benefit for patients. More recently, we had our first positive trial, not just in the disease-free survival metric, but with OS as well: the KEYNOTE-564 study of adjuvant pembrolizumab.

There are other immune checkpoint inhibitor trials that did not show a similar benefit. When you look into each trial, you can create pretty reasonable explanations for why KEYNOTE-564 [was positive and the others were not]. It’s the way [pembrolizumab was] given for a full year plus its eligibility criteria [that explains] why it might have been a successful trial where some of the other ones did not show benefit.

We have to also acknowledge the limitations [of the study]. We don’t know exactly what all the patients had subsequently received, maybe not all of those patients got immunotherapy later on. But when we take the study in aggregate, it’s certainly a positive trial, though some of the benefits are modest, particularly for patients with intermediate- to high-risk disease.

This is a milestone moment, it’s the first adjuvant trial that improves OS for patients with kidney cancer. I hope it’s the first of a whole slew of new options for patients. I know that there are many trials now that are seeking to expand on using pembrolizumab as a backbone and trying to see if we can do even better because there’s certainly a need to do better.

Do you see any other therapeutics under the immunotherapy umbrella having an impact in kidney cancer?

One of the things I [spoke] about at ASCO is the current and future landscape of immunotherapy in kidney cancer. I use a model for thinking about immunotherapy, which is that we have this car full of T cells and we’re trying to drive that car towards the tumor to have effective anti-tumor immunity. When we think of that simplified model, and the things we can do to help modulate and improve anti-tumor activity, we can press on the gas pedal and make the car go faster. That’s essentially what the initial generation of cytokine therapies did.

That was the initial attempt and those were somewhat effective but crude tools. There’s a whole new generation of engineered cytokines that try to more precisely press on that gas pedal, for instance modified versions of IL-2 that directly target the IL-2 to CD8 cells rather than broadly giving it to all cells and other things such as engineered versions of IL-18 which have shown some promise in preclinical studies.

The second big pocket is releasing the brakes and that’s where our current generation of immune checkpoint inhibitors come in, with the main brake being the PD-1 axis. We know CTLA-4 is another axis with ipilimumab. But there’s a whole host of other brakes or immune checkpoints that we can begin to address, [including] some that are under active investigation. Checkpoints such as TIGIT or LAG3 are promising and need further investigation. [Other approaches] are also hopefully on the horizon, such as HHLA2 and other checkpoints that are just starting to emerge that we need to keep an eye on as they move from the laboratory towards the clinic.

We have the gas pedal, we have the brakes, and the step is adding a steering wheel. This has been something that’s been less commonly used in kidney cancer, though we’re starting to see some areas of success. The way to do this is with antigen-directed therapies. When you know the target of those T cells, you can begin to, either through an engineered cell therapy approach [such as] CAR T-cell therapy or through a vaccine-based approach, really steer the immune system towards those tumor cells.

References

1. Choueiri TK, Tomczak P, Park SH, et al. Overall survival with adjuvant pembrolizumab in renal-cell carcinoma. N Engl J Med. 2024;390(15):1359-1371. doi:10.1056/NEJMoa2312695
2. FDA approves pembrolizumab for adjuvant treatment of renal cell carcinoma. FDA. November 17, 2021. Accessed May 30, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-adjuvant-treatment-renal-cell-carcinoma