Early Data With DFF332, Other Key Biomarker Analyses Continue to Inform Approaches in RCC

With the continued expansion of immunotherapies and targeted therapies in renal cell carcinoma (RCC), biomarker analyses are crucial for developing more informed, individualized treatment strategies in both metastatic and localized settings, according to Sumanta Kumar Pal, MD, FASCO.¹

At the 2024 ASCO Annual Meeting, results from a phase 1, first-in-human study (NCT04895748) evaluating the HIF2α-targeted small molecule therapy DFF332 in adult patients with advanced clear cell RCC were presented. DFF332 monotherapy was shown to be safe and well tolerated across all doses and schedules, with no dose-limiting toxicities or grade 4 treatment-related adverse effects reported. The disease control rate in the treated population (n = 40) was 52.5%, and treatment was ongoing in 27.5% of patients at the data cutoff date of January 15, 2024. Moreover, early signals of antitumor activity were observed with DFF332 at daily doses; this included 2 patients who experienced a confirmed partial response and 19 patients who achieved stable disease as their best response. The study was stopped prior to the identification of an optimal dose of DFF332, and biomarker analyses are ongoing.

Although DFF332 did not initially demonstrate strong efficacy signals vs other agents in the pipeline, such as belzutifan (Welireg), it did have a favorable toxicity profile, Pal explained.

“My hope is that the DFF332 approach may be palatable in combination with other therapies,” Pal added during an interview with OncLive^® regarding this research. Pal serves as chair of the Kidney and Bladder Cancer Disease Team, co-director of the Kidney Cancer Program, and a professor in the Department of Medical Oncology and Therapeutics Research at City of Hope, in Duarte, California.

In the interview, Pal highlighted key research efforts underway in the RCC treatment paradigm, including early data with DFF332 and its potential use in combination regimens; the importance of optimizing therapies for non–clear cell RCC and identifying predictive biomarkers to address unmet needs; and the value of recent biomarker analyses from several major trials presented during the ASCO Annual Meeting.

OncLive: What is unique about the mechanism of action of DFF332?

Pal: DFF332 is an agent that, much like belzutifan and other therapies, actually blocks HIF2a. It’s an orally administered agent that’s taken daily or weekly in the context of the trial that we explored. In this phase 1 dose-escalation trial, we looked at a relatively large cohort of patients with metastatic RCC.

What efficacy and safety results were reported with DFF332 in this phase 1 study?

We’ve actually made our way through dose escalation with no substantial evidence of hypoxia and not a lot of severe anemia thus far, which makes it relatively unique. Having said that, the response rates that we saw weren’t necessarily comparable to what we see with belzutifan. However, this was a very heavily pretreated population of patients, and that’s important to bear in mind. [In the future,] this may be something that we’ll see used, for instance, in combination with other targeted therapies or immune checkpoint inhibitors.

What unmet needs still exist for patients with RCC?

There are so many unmet needs that remain for patients with RCC. I would say that one of the key unmet needs is non–clear cell kidney cancer. We need to do a better job of understanding what optimal therapies are [for that disease]. Many of the studies that we’ve done to date, including ones that I’ve led, unfortunately, have insufficient power to make definitive determinations around what the best therapy is, so that [insight] would be extremely helpful. Another unmet need in kidney cancer is biomarkers, and that’s one of the reasons [I was] so excited about the 2024 ASCO Annual Meeting. Understanding biomarkers that might predict response to [a given agent] for metastatic disease might potentially help guide which treatment regimen we’re using, so we can do this in a much more informed fashion. Those are probably the 2 principal issues, but there are many, many others that we still need to focus on [addressing] in this field.

What were some of the key biomarker analyses in RCC presented during the meeting?

I tend to focus my clinical practice on kidney cancer, and there’s a lot of really exciting stuff [that was] presented at [the] meeting, in particular some of the biomarker data. For instance, there were several oral presentations distilling the biomarker data from the phase 3 CLEAR trial [NCT02811861], which is the analysis of lenvatinib [Lenvima] and pembrolizumab [Keytruda] in patients with advanced RCC. There’s also the phase 3 KEYNOTE-426 study [NCT02853331], which looks at axitinib [Inlyta] combined with pembrolizumab [Keytruda].

Then, there is a study that I led, which [was] presented by Laurence Albiges, MD, of Gustave Roussy—[the] phase 3 IMmotion010 [NCT03024996] trial of adjuvant atezolizumab [Tecentriq]. Although the study [did not meet] its primary end point, it did show that KIM-1, which is a circulating biomarker, is an excellent predictor of outcome with adjuvant therapy. This is exciting from the standpoint that we’ll have some data for abstracts that are covering metastatic disease and biomarkers to predict response, which is hugely important, but also potentially some biomarkers in the localized setting that might help us guide the use of adjuvant treatments.

Reference

Pal SK, Tannir NM, Grell P, et al. Preliminary safety, pharmacokinetics and clinical activity of DFF332, an oral HIF2α inhibitor, as monotherapy in a phase 1 dose escalation study in patients with advanced clear cell renal cell carcinoma. J Clin Oncol. 2024;42(suppl 16):4513. doi:10.1200/JCO.2024.42.16_suppl.4513