Investigational Remedies for Refractory RCC Develop Past Immunotherapy

Brian I. Rini, MD

Hypoxia-inducible issue (HIF) and AXL inhibition may fit synergistically with checkpoint inhibitors to learn sufferers with refractory renal cell carcinoma (RCC), in accordance with Brian I. Rini, MD. Analysis is investigating novel therapy mechanisms on this inhabitants past people who sufferers have already progressed on, akin to PD-1 inhibitors like pembrolizumab (Keytruda) or VEGF TKIs like sorafenib (Nexavar).

“The subsequent wave of advances in kidney most cancers is extra more likely to be within the refractory setting than within the entrance line,” mentioned Rini.

In an interview with OncLive®, Rini mentioned commonplace and investigational therapy choices for sufferers with RCC who’re refractory to immunotherapy; the potential function of biomarkers in future focused therapies; and the necessity for novel mechanisms akin to HIF inhibition to fulfill the wants of sufferers who don’t reply to immunotherapy or VEGF TKIs.

The part 3 TIVO-3 trial (NCT02627963) established tivozanib (Fotivda) as a later-line commonplace of care (SOC), as sufferers with superior RCC who acquired the agent had a median progression-free survival (PFS) of 5.6 months vs 3.9 months with sorafenib.1 Rini defined how this trial supported using TKIs in refractory RCC and defined remaining wants on this inhabitants. He elaborated on novel brokers beneath analysis on this setting, such because the part 3 MK-6482-005 trial (NCT04195750), which is investigating the efficacy of belzutifan (Welireg) vs everolimus (Afinitor) in sufferers with superior RCC who’ve progressed on prior VEGF-targeted therapies and PD-1 or PD-L1 inhibitors.2

Rini is a professor of medication within the Division of Hematology Oncology at Vanderbilt College Medical Middle in Nashville, Tennessee.

OncLive®: What does therapy sequencing presently appear like in RCC, and what unmet wants stay relating to efficient later-line therapies?

Rini: Most sufferers will obtain an immune-based doublet as frontline remedy for kidney most cancers. A number of trials present a survival benefit [with this approach]. Barring contraindications, [most] frontline kidney cancers will probably be handled with an immune remedy, which implies that once we’re speaking about refractory kidney most cancers, we’re speaking about immune-refractory kidney most cancers.

Proper now, the unexciting SOC [in the refractory setting] is single-agent VEGF TKIs. A number of research, which weren’t carried out within the TKI-refractory setting however have been carried out within the basic refractory setting, confirmed exercise with numerous TKIs. One [may not be] meaningfully higher than the opposite. Practitioners decide principally primarily based on [factors such as] familiarity and adversarial impact [AE] profile. All practitioners have their favorites.

The TIVO-3 research investigated tivozanib vs sorafenib within the third- and fourth-line settings. A couple of quarter of these sufferers have been immune refractory. That is 1 of the largest datasets [in this setting], though it [comes from] a subset of immune-refractory sufferers. This trial confirmed benefits with tivozanib that led to its FDA approval.

[There are some] rising knowledge in a extra fashionable inhabitants, however nonetheless with a single-agent TKI. The largest query the sphere has proper now could be whether or not a affected person can profit from immune remedy after having progressed on prior immune remedy.

Single-arm knowledge with the mix of lenvatinib [Lenvima] and pembrolizumab present exercise, however they’re single-arm knowledge. We don’t know whether or not that [activity is] simply from the lenvatinib or whether or not pembrolizumab is contributing to that doublet. Two randomized trials, 1 that has accomplished accrual and 1 that’s ongoing, will hopefully deal with this query.

The [phase 3] CONTACT-03 trial [NCT04338269] is investigating cabozantinib [Cabometyx] plus atezolizumab [Tecentriq] vs cabozantinib in immunotherapy-refractory sufferers. It accomplished accrual and we may even see PFS and total survival knowledge within the subsequent 12 months. The continued trial is investigating tivozanib plus nivolumab [Opdivo] vs tivozanib in the same immunotherapy-refractory setting. Each trials included sufferers who progressed on adjuvant pembrolizumab, which is an rising immunotherapy-refractory inhabitants.

These 2 trials [will be] vital [for determining] whether or not sufferers having 2 probabilities at immune remedy means they’ve 2 probabilities at a treatment. Once I change from an immune-based routine to a non–immune primarily based routine, I’m not pondering I can treatment the affected person. I’m simply making an attempt to manage the illness. It’s a totally different mindset when it comes to [factors like] strategy and tolerance of AEs. Hopefully within the subsequent 12 to 18 months, we’ll have 2 massive trials that deal with that vital query.

[Regarding novel therapies], belzutifan, a HIF inhibitor, is now authorized in von Hippel-Lindau syndrome. A number of trials are ongoing, most notably within the refractory setting, [such as 1 investigating belzutifan] monotherapy vs everolimus with registrational intent, in addition to doublets and triplets [with belzutifan]. [Belzutifan is] an energetic drug, and it’s actively being developed in kidney most cancers.

Different mechanisms embrace different checkpoint inhibitors. We’ve labored with an AXL inhibitor, batiraxcept [AVB-S6-500]. Different medication are directed at metabolism. Many mechanisms are being investigated within the refractory setting. HIF inhibition with belzutifan is probably the most developed, however a number of others are in that promising part 1/2 class.

How would possibly novel combos affect the refractory RCC therapy panorama sooner or later?

They’re not affecting it but as a result of they’re nonetheless in early-phase research. Some will pan out and a few received’t. Nevertheless, [regarding unmet needs and drug development] in kidney most cancers, now we have many immune brokers and VEGF inhibitors, however we want different mechanisms. HIF inhibition is expounded to VEGF inhibition, however is distinct. We’d like novel mechanisms, as a result of there’s most likely an entire biologic subset of sufferers who aren’t immune responsive and aren’t VEGF responsive. They’re omitted, and so they produce other mechanisms driving their tumors. We have to uncover what these mechanisms are and goal them. It’s good to see different mechanisms being developed.

What unmet wants exist relating to efficient biomarker-based therapies in RCC?

Biomarkers are an enormous matter. The brief abstract is that now we have no clinically helpful biomarkers in kidney most cancers. PD-1 and PD-L1 expression didn’t turn into helpful. They most likely enrich for response to immune remedy, particularly the ipilimumab [Ipilimumab]/nivolumab doublet, however clinically, we’re not utilizing PD-L1 to pick out sufferers as a result of sufferers with PD-1–adverse illness nonetheless profit.

Sarcomatoid histology is an efficient biomarker for response to ipilimumab/nivolumab. I take advantage of that, and clinically, it’s 1 of our greatest biomarkers. Nevertheless, now we have but to develop true biomarkers which might be choosing for 1 remedy or in opposition to one other remedy in kidney most cancers, though large efforts are ongoing. We’re doing a greater job of investigating that than now we have previously.

Within the frontline [phase 2] OPTIC RCC research [NCT05361720], we’re taking newly identified sufferers, biopsying metastatic tissue, working RNA sequencing on that tissue, and figuring out their cluster, a biologic task that got here out of an evaluation of the part 3 IMmotion151 research [NCT02420821]. These clusters are both extra angiogenic or extra immune inflammatory. We’re taking the angiogenic cluster sufferers, about 30% or 40% of sufferers, and treating them with cabozantinib/nivolumab, a normal frontline routine that has a VEGF inhibitor. The immune [inflammatory cluster] sufferers, round 20% or 25% of sufferers, are getting ipilimumab/nivolumab.

The speculation is that we will enhance response charges in contrast with historic controls by enriching for the appropriate biology and matching that biology to therapy. That trial is up and working. We’ve screened many sufferers and are accruing. That is an instance of the place we have to go. Though that biomarker might be not good, we’ll refine it. We’re at the very least making an attempt to deal with sufferers primarily based on their biology and never medical elements, physician bias, or different strategies we have a tendency to make use of proper now.

What’s your most important message for colleagues relating to the way forward for refractory RCC therapy?

A lot consideration has been paid within the frontline setting over the previous 5 years with massive trials which have redefined the SOC. Nevertheless, now, a lot of the eye is transferring towards that refractory house, which has been a bit uncared for. Massive part 3 trials [are ongoing] with novel mechanisms like HIF inhibition. Hopefully, within the subsequent 12 to 18 months, this refractory panorama will probably be redefined.


Rini BI, Pal SK, Escudier BJ, et al. Tivozanib versus sorafenib in sufferers with superior renal cell carcinoma (TIVO-3): a part 3, multicentre, randomised, managed, open-label research. Lancet Oncol. 2020;21(1):95-104. doi:10.1016/S1470-2045(19)30735-1 A research of belzutifan (MK-6482) versus everolimus in members with superior renal cell carcinoma (MK-6482-005). Up to date August 1, 2022. Accessed February 14, 2023.

Editor’s Word: This interview was carried out previous to the 2023 Genitourinary Cancers Symposium.