Entering an Era of Immunotherapy-Based Combinations for Metastatic RCC

The frontline treatment landscape of renal cell carcinoma (RCC) is exploding with immunotherapy-based options, according to Tian Zhang, MD, who added that with this growth, the need for up-front risk stratification, careful monitoring of associated toxicities, the identification of new biomarkers, and further understanding on opportunities for discontinuation, are all underscored.

“It is very important to risk stratify our patients up front and figure out which patients would benefit from immunotherapy combinations,” Zhang said. “We know some special populations of metastatic clear cell carcinoma, such as those with sarcomatoid disease, benefit from [these] treatments…We are really coming into a different era of immunotherapy-based treatments for patients with metastatic kidney cancer.”

In an interview with OncLive® during a 2021 Institutional Perspectives in Cancer webinar on genitourinary cancers, Zhang, a medical oncologist and assistant professor of medicine at Duke Cancer Institute, discussed key considerations regarding frontline immunotherapy-based combinations in RCC and recent data from pivotal trials examining their use.

OncLive®: What are some of the key advances made with immunotherapy-based regimens in frontline RCC treatment?

Zhang: We have had multiple first-line metastatic RCC trials that all have been controlled with patients treated with sunitinib [Sutent]. Sunitinib was certainly the standard of care for many of our patients through the 2010s, so this was the control cohort used in all these studies. All these studies enrolled patients with clear cell kidney cancer with measurable, metastatic disease and no prior systemic therapies, and then randomized them to an immunotherapy-based combination.

The phase 3 Checkmate-214 trial [NCT02231749] was the initial trial, which examined ipilimumab [Yervoy] plus nivolumab [Opdivo] and read out in 2017. Then, we had the phase 3 JAVELIN Renal 101 trial [NCT02684006], [which examined] axitinib [Inlyta] with avelumab [Bavencio], and the phase 3 KEYNOTE-426 trial [NCT02853331], [which evaluated] axitinib with pembrolizumab [Keytruda]; these trials read out in 2019.

In between, we also saw the combination of atezolizumab [Tecentriq] with bevacizumab [Avastin] in the phase 3 IMmotion151 trial [NCT02420821]. Unfortunately, that [trial] did not show an overall survival [OS] benefit, and thus, this is not one of the currently approved regimens.

[We saw data from] the phase 3 CheckMate-9ER trial [NCT03141177], which looked at the combination of cabozantinib [Cabometyx] and nivolumab, presented during the 2020 ESMO Virtual Congress. Most recently, [findings from] the phase 3 CLEAR trial [NCT02811861] were reported; [results showed that] the combination of lenvatinib [Lenvima] and pembrolizumab improved progression-free survival [PFS], OS, and response rate.

Could you expand on the data that read out from the CLEAR trial?

In the CLEAR trial, patients were randomized to receive 1 of 3 treatment cohorts. The first was the combination of lenvatinib plus pembrolizumab, with lenvatinib starting at 20 mg daily. The second cohort was treated with lenvatinib plus everolimus [Afinitor], which is an approved combination strategy in VEGF-refractory RCC. Then the third was the control cohort of patients treated with sunitinib at 50 mg, 4-weeks-on and 2-weeks-off.

The CLEAR investigators enrolled more than 1000 patients, so approximately 350 per cohort, and treated them with these different [regimens], and what we saw was an improvement in PFS. Lenvatinib/pembrolizumab compared with sunitinib had a hazard ratio [HR] of 0.39, which was statistically significant, and the median PFS was 23.9 months vs 9.2 months, respectively. We also saw an improvement in OS for patients treated with lenvatinib/pembrolizumab compared with sunitinib, with a HR of 0.66. In that specific instance, the median OS had not been reached, as of the median cut-off of about 27 months.

The important efficacy end point for lenvatinib/pembrolizumab was its improved objective response rate [ORR]. Complete and partial responders made up 71% of all patients treated with [the doublet]. Only 5% of patients had progressive disease as their best response. Therefore, approximately 95% of patients had some disease stability on the combination of lenvatinib/pembrolizumab and that's very important when we are thinking about early disease control for patients with aggressive metastatic RCC.

Some treatment-related adverse effects [AEs] were very specific to lenvatinib like hypertension, stomatitis, hand–foot syndrome—all of the things that we associate quite a bit with VEGF inhibitors. We also saw some AEs that can be attributable to either lenvatinib or pembrolizumab, and those included diarrhea, hypothyroidism, fatigue, and even rashes. It is very important for patients who are being treated with lenvatinib and pembrolizumab to be monitored closely during treatment for these AEs and managed early, so that they can remain on [the combination] for longer periods of time.

How does risk factor into the effectiveness of these immunotherapy regimens?

As we look across all these frontline phase 3 trials that are [examining] immunotherapy-based [regimens], we are seeing that the mature OS improvements are really driven by the patients who have metastatic kidney cancer with International Metastatic RCC Database Consortium [IMDC], intermediate- and poor-risk disease, [and less so with those] who have favorable-risk disease.

This is a group of patients who have more inflammatory tumors with anemia, neutrophilia, or thrombocytosis, or who have some marker of bone metastases, like hypercalcemia, that we know to be associated with poor prognosis in metastatic disease. Finally, the, the other IMDC risk factor to note is the time from diagnosis to treatment of less than 1 year, so many of the de novo metastatic RCC types of populations. These patients also perform poorly and really benefit from immunotherapy up front and in some combination or another.

Are any biomarkers under examination to inform which patients will benefit most from immunotherapy-based approaches? What is known thus far?

Biomarkers are a really key question. Unfortunately, we have limited molecular markers to help us stratify patients who might respond to immunotherapies vs those who will not. However, across all of these phase 3 trials, we are seeing that the sarcomatoid differentiation is picking up a group of patients that are more likely to be immunogenic and immuno-responsive.

As we look at Checkmate-214, KEYNOTE-426, and IMmotion151, all have reported on subsets of patients with sarcomatoid differentiation, who have had more benefit from the immunotherapy combination compared with sunitinib. As such, that is one population of patients who will probably respond more to an immunotherapy-based combination.

What is some of the work that is being done to examine when treatment with immunotherapy should be stopped?

Many of these [frontline] trials [gave] treatment until disease progression or unacceptable toxicities. The most mature data we currently have is from CheckMate-214, where investigators followed patients after treatment discontinuation. [We saw that] patients who stopped nivolumab [after achieving] a partial or complete response at 2 years were more likely to remain off treatment. About 42% of these patients are still off treatment at 2 years compared with those who stopped their immunotherapies for stable disease, but likely unacceptable toxicities. More than 75% of patients with stable disease were restarted on another treatment. This treatment-free survival interval is a very important clinical time point for our patients and it’s clinically meaningful; it's a time when patients are off of treatment and are not experiencing AEs related to therapy.

At the 2021 Genitourinary Cancers Symposium, we also saw some of the discontinuation data for patients treated with pembrolizumab and axitinib in the KEYNOTE-426 study. The trial protocol mandated pembrolizumab discontinuation at 2 years. [Investigators] followed that population of patients who reached 2 years and discontinued and found that these patients were younger, so under 65 years; they had better performance status; and they usually had favorable- or intermediate-risk disease. Also, we [saw] that the [patients with] sarcomatoid histology were more likely to finish out the 2 years without disease progression and actually get to treatment discontinuation.

With these studies, we are learning a lot about patients when we stop treatment; [we know more about] which patients can stop treatment, and when we do stop treatment, what to look out for. All these clinical end points are really helping us to counsel patients about potential immunotherapy discontinuation in day-to-day practice.