Updated Data Continue to Aid IO-Based Frontline Treatment Decisions in Advanced RCC

Selecting and sequencing treatments remain complex decisions for patients with advanced renal cell carcinoma (RCC); however, the continued emergence of data have helped shed light on which agents and combinations may provide the most benefit to different patients in this population, according to Tian Zhang, MD, MHS.

“[Data regarding the phase 3 KEYNOTE-426 (NCT02853331), CLEAR (NCT02811861), and CONTACT-03 (NCT04338269)] were cases that we discussed that have helped inform our practice, and these trials that were reported out at the 2023 ASCO Annual Meeting certainly help us make decisions for patients in the clinic with kidney cancer,” Zhang said in an interview following an OncLive® State of the Science Summit™ on bladder cancer and RCC chaired by Hans Hammers, MD, PhD.

In the interview, Zhang detailed how updated data presented at the 2023 ASCO Annual Meeting from trials such as KEYNOTE-426 and CLEAR have showed the sustained efficacy of VEGF plus immunotherapy combinations vs sunitinib (Sutent) in the first-line setting; discussed where the immunotherapy-only combination of ipilimumab (Yervoy) and nivolumab (Opdivo) fits in the frontline setting; and highlighted how data from CONTACT-03 provided key insights on the use of immunotherapy in patients with advanced RCC after progression on a prior immune checkpoint inhibitor.

Zhang is an associate professor in the Department of Internal Medicine at UT Southwestern Harold C. Simmons Comprehensive Cancer Center in Dallas, Texas.

OncLive: Regarding your presentation on the treatment of patients with advanced RCC, what does the process look like for selecting immunotherapy-based combinations in the first-line setting? 

Zhang: We talked quite a bit about the first-line management for metastatic kidney cancer, particularly in light of the ASCO data that were presented and the follow up for KEYNOTE-426 and CLEAR. We focused on the selection process for immunotherapy-based treatments with ipilimumab/nivolumab vs a VEGF inhibitor/immunotherapy combination such as axitinib [Inlyta] plus pembrolizumab [Keytruda] used in KEYNOTE-426 and lenvatinib [Lenvima] pls pembrolizumab used in CLEAR.

In one of the discussion cases that came up, we were thinking through [a case] for a patient with more symptomatic disease and de novo metastatic disease, where early disease control was important; therefore, we might reach for a VEGF/immunotherapy combination such as axitinib/pembrolizumab or lenvatinib/pembrolizumab.

At ASCO, we saw the 5-year OS data for KEYNOTE-426, showing a benefit for pembrolizumab/axitinib over sunitinib, and the 4-year OS data of CLEAR, showing an OS benefit of lenvatinib/pembrolizumab over sunitinib. Both [sets of data] had already shown early disease control with improvements in PFS.

Of note, there is still a patient population where we would choose to treat with ipilimumab/nivolumab, a pure immunotherapy doublet. These patients tend to have less symptomatic disease and less tumor burden in general, and they’re shooting for a potential complete response from their treatments. Most of the time when we’re having these conversations with patients who [may receive] ipilimumab/nivolumab in the frontline setting, these are also patients who are not interested in the longer-term toxicities [associated with] VEGF inhibitors.

How could data from the CONTACT-03 trial help inform care?

At the 2023 ASCO Annual Meeting, the CONTACT-03 trial was presented in refractory RCC, and CONTACT-03 was based off the [phase 1/2] COSMIC-021 basket trial [NCT03170960], where cabozantinib [Cabometyx] with atezolizumab [Tecentriq] showed promising responses, even in the refractory setting.

CONTACT-03 was a phase 3 trial that enrolled patients who had [received and progressed on] prior immunotherapy-based regimens, and [patients were] randomly assigned to cabozantinib plus atezolizumab vs cabozantinib [alone]. It showed that there were not many differences in this patient population if treated with cabozantinib/atezolizumab vs cabozantinib monotherapy. Interestingly, there was no difference in either PFS or the early OS analysis for the control cohort of cabozantinib monotherapy vs the combination.

Of note, this was a bit of a heterogeneous patient population—the trial allowed both [patients with] clear cell kidney cancer as well as non–clear cell kidney cancer. There was approximately 11% to 12% of each cohort that were of non–clear cell [histology], so that might have diluted the effect. Additionally, the first-line treatment options that these patients had undergone were different; approximately 35% of patients in each cohort had received pure immunotherapy combinations and were not VEGF [exposed], and cabozantinib, as we know from prior trials, has really good effect for VEGF-naïve patient populations.

In your practice, what are some of the patient and disease characteristics that could prompt the use of radiation in the oligometastatic setting?

Dr Hammers presented a case [of] a set of patients with oligoprogression in kidney cancer, and at UT Southwestern, we have specifically looked at oligoprogressive disease and [evaluated] using radiation therapy to oligometastatic sites that potentially can hold off further systemic treatments.

In our practice, we share and make that multidisciplinary decision with the patient. Patients who have less than 4 oligometastatic sites and those who are [hesitant to] take on the systemic toxicities of either immunotherapies or VEGF-targeted therapies are often highly motivated to receive radiation instead to hopefully hold off on using systemic treatments. It is a multidisciplinary conversation where we present the options for patients. As they’re getting radiation and are in follow-up, we’re also following closely. If patients do have progressive disease afterward, [then] we’re following carefully to use systemic therapies.

Raquibul Hannan, MD, PhD, is leading a trial in the ECOG-ACRIN group called [the phase 3] SOAR trial [NCT05863351]. It is about to launch, and it is looking at radiation for patients with oligometastatic kidney cancer to try to prolong the time before the need for systemic treatments and [reduce] systemic AEs that are incurred with more of our systemic agents.