Pal Previews Potential Second-line and Beyond Options in RCC

Although a great deal of progress has been made in the frontline treatment of patients with renal cell carcinoma (RCC), more options are needed in the second-line setting and beyond, according to Sumanta K. Pal, MD. In an effort to address this need, efforts are examining cabozantinib (Cabometyx) combinations, the VEGF tyrosine kinase inhibitor (TKI) tivozanib (Fotivda) and hypoxia-inducible factor–2 alpha (HIF-2α) inhibitors like belzutifan (MK-6482), and chimeric antigen receptor (CAR) T-cell therapies.

“Several studies are emerging in the second-line space, [and these approaches] warrant further investigation. [We have not seen] any slam dunks yet,” Pal noted. “We are intrigued by the possibility of cabozantinib with glutaminase inhibitors [such as] telaglenastat [CB-839]. [However], seeing the phase 3 study [examining this regimen] fail signals to me that we really must look at other avenues. Studies like the CONTACT-03 trial [NCT04338269] are great potential outlets. I would also look to CAR T-cell therapy trials or [efforts that are] using HIF-2α inhibitors.”

The phase 3 CONTACT-03 trial is examining the use of cabozantinib alone or in combination with atezolizumab (Tecentriq) following progression on or after an immune checkpoint inhibitor in patients with advanced or metastatic RCC. Pal, the trial’s principal investigator, shared that he and his team seek to shed light on an important area of interest in practice.

“This is a fascinating study because it emulates something that I see happening a lot in the clinic: patients continuing on immunotherapy, despite failure of immunotherapy in the frontline setting,” Pal said. “We really need to arrive at a conclusion as to whether that is a beneficial practice.”

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on genitourinary cancers, Pal detailed ongoing research efforts dedicated to providing additional therapeutic options for patients with RCC in the second-line setting and beyond. A medical oncologist, Pal is also a clinical professor in the Department of Medical Oncology and Therapeutics Research and codirector of the kidney cancer program at City of Hope.

OncLive®: The combination of atezolizumab plus cabozantinib has shown promise in non–clear cell RCC. What are the next steps with this regimen?

Pal: I have been really impressed by the data [reported with] cabozantinib/atezolizumab in non–clear cell kidney cancer. We see response rates upward of 25%. Specifically, among those with papillary kidney cancer or those with chromophobe RCC, we have seen some really interesting and protracted responses [with this regimen]. It really begs the question of whether we can look to this particular regimen [for use] in a couple of unique settings.

For instance, we are now designing a study that will look at cabozantinib, which through SWOG 1500 [NCT02761057] has really been established as the standard of care for [patients with] papillary disease, with or without atezolizumab. I am hoping that this study is going to move forward relatively quickly. We are dovetailing on PAPMET [NCT02761057] and calling it PAPMET-2. Hopefully, that study will really evoke some change for [patients with] non–clear cell histologies.

COSMIC-021 (NCT03170960) is also examining this combination. To date, what has the safety profile looked like with this regimen?

COSMIC-021 is a very expansive effort to examine the combination of cabozantinib and atezolizumab, not just in genitourinary cancers like bladder, prostate, and kidney cancer, but also in lung cancer, breast cancer, and a whole host of other malignancies.

Thus far, I really have not seen any unexpected toxicities from the reported data sets with the combination. It seems to me that the anticipated safety profile is fairly consistent across the histologies that have been reported to date and consistent with the reported experiences of cabozantinib and atezolizumab individually.

What was the significance of the TIVO-3 trial (NCT02627963)?

The TIVO-3 data set is a really important one; it dovetails on TIVO-1 [NCT010307833], which was a frontline study that reported out several years ago. That trial had compared tivozanib with sorafenib [Nexavar] and actually met its primary end point, [demonstrating an] improvement in progression-free survival [PFS]. However, [we saw] a concerning overall survival signal in that study, where the data seemed to favor sorafenib.

Now, in this most recent iteration of TIVO-3, we have reported out data suggesting that tivozanib improves PFS relative to sorafenib; it also looks as though survival is equivalent between the 2 arms, with a hazard ratio [HR] below 1 [pointing toward] tivozanib.

Tivozanib also proved to maintain efficacy, irrespective of a patient’s prior TKI exposure. Could you speak to the significance of those findings?

One of the most important subset analyses of the tivozanib study was presented by Brian Rini, MD, of Vanderbilt University Medical Center, and looked at patients who had previously received axitinib [Inlyta]. That is so vital [because] patients who have received prior axitinib were thought to maybe have received a drug almost akin to tivozanib; the receptor profiles are similar, so [the thought is] that perhaps tivozanib would have activity in the same settings as axitinib. However, in point of fact, when you look at the data, it seems that the HR of benefit remains consistent, irrespective of prior axitinib [exposure]. We can probably carve out a niche for tivozanib after any TKI.

Several other trials are being done in the second-line setting and beyond. Are any other efforts particularly promising?

One is the CONTACT-03 trial, which is specifically being done in the [second-line] setting; it looks at cabozantinib plus or minus atezolizumab. I am also very intrigued by the prospect of other really novel modalities, [such as] HIF-2α inhibitors and CAR T cells in RCC. So many interesting avenues are moving forward that we can potentially [utilize] in patients who are not responding to conventional treatments. Frankly, we really need more options.

Where should future research efforts be focused?

We have [made a lot of headway] in the frontline [treatment of] patients with kidney cancer. I am really passionate about non–clear cell kidney cancer and moving things forward in that space. [I am also interested in research being done] in the second- and third-line settings. We have a lot of work to do to show that we can improve outcomes for patients who, in most cases, will inevitably progress and need second- and third-line treatments. We are just not there yet, in terms of having great options available.

Reference

Pal S, Albiges L, Suárez C, et al. CONTACT-03: randomized, open-label phase III study of atezolizumab plus cabozantinib vs cabozantinib monotherapy following progression on/after immune checkpoint inhibitor (ICI) treatment in patients with advanced/metastatic renal cell carcinoma (RCC). J Clin Oncol. 2021;39(suppl 6):TPS370. doi:10.1200/JCO.2021.39.6_suppl.TPS370