Commentary

Article

Braun Spotlights Novel Treatment Developments in RCC

Author(s):

David A. Braun, MD, PhD, highlights the developing role of T-cell therapies in RCC and looks toward the horizon for other advances.

David A. Braun, MD, PhD

David A. Braun, MD, PhD

The development of new therapies for patients with renal cell carcinoma (RCC), including engineered T-cell therapies, has caught the attention of investigators, according to David A. Braun, MD, PhD.

“We’ve seen a couple of CAR T-cell [therapy] trials published, or at least presented [during medical meetings],” Braun noted. “The [phase 1] COBALT-RCC [NCT04438083] and TRAVERSE [NCT04696731] trials are both [evaluating agents] targeting CD70, which is commonly expressed on clear cell RCC.”

During the 2024 AACR Annual Meeting , investigators presented findings from COBALT-RCC, which examined the allogeneic CAR T-cell therapy CTX130 in patients with advanced clear cell RCC. At the October 9, 2023, data cutoff, results from the study demonstrated that 1 patient who was treated at the lowest dose level of 3 x 107 CAR T cells achieved a complete response (CR) at 3 months; the CR was maintained at 36 months. In the overall cohort (n = 16), most patients achieved stable disease (75%) and the disease control rate (DCR) was 81.3%. The median progression-free survival (PFS) was 2.9 months (95% CI, 1.7-6.0), and the median overall survival was 20.5 months (95% CI, 14.3-not evaluable).1

Preliminary findings from TRAVERSE, which were presented during the 2023 AACR Annual Meeting, showed that the allogeneic CAR T-cell therapy ALLO-316 displayed efficacy and tolerability in patients with advanced or metastatic RCC. At a median follow-up of 7.8 months (range, 0.4-18.1), efficacy-evaluable patients (n = 18) achieved an objective response rate of 17% and a DCR of 89%. Notably, the DCR in patients with CD70-positive disease (n = 10) was 100%, including 3 patients with partial responses. The median PFS among all patients was 5 months.2

In an interview with OncLive, Braun, assistant professor, medicine (medical oncology), Louis Goodman and Alfred Gilman Yale Scholar, member, Center of Molecular and Cellular Oncology, at Yale Cancer Center in New Haven, Connecticut, discussed the standing of the investigational CAR T-cell agents and other areas of interest in RCC following the 2024 ASCO Annual Meeting.

OncLive:What research is catching your eye in the engineered T-cell therapy space in RCC?

Braun: COBALT-RCC was published recently [and] it’s an interesting proof of principle. [The investigational agent] didn’t have huge response rates, but there was one CR that was durable lasting over 3 years. It’s not the end of the story, but just the beginning, [providing] a proof of concept that you can use cell therapies like CAR T to have an antigen-directed response. In TRAVERSE, we’re seeing response rates that are starting to creep up a bit. That’s something to certainly keep an eye on.

Our group’s work has been focused on vaccine-based approaches, [such as] neoantigen vaccines. We’ve looked to see what the unique targets of a tumor cell are and if we can give a personalized vaccine that might help direct those T cells against the tumor. That’s a whole area that we’ll see [develop] hopefully in the coming years.

[Another area of interest] is modulating all those things that are extrinsic to T cells, [such as] myeloid suppression or unfavorable microbiome, all these sorts of things that can negatively affect T-cell function. We’re probably already seeing the first iterations of that, certainly some ideas in terms of myeloid targeting and some interesting work in the microbiome space as well. We’ve seen over the past couple of years CBM 588, [which is a] live bacterial product containing the spore forming bacterium clostridium butyricum. When it’s added to first-line regimens it seems to improve clinical outcomes.

These are very small trials, so we have to be cautious. But in 2 independent studies, one published in Nature Medicine and a second that was presented at the 2023 ASCO Annual Meeting, when CBM 588 was added to a standard of care regimen those clinical outcomes improved. When I think about the next few years in terms of immunotherapy for kidney cancer, I believe and hope we’ll see [continued] development of engineered cytokines, new immune checkpoint inhibitors, antigen-directed therapies and ways to modulate T-cell extrinsic factors.

What translational and biomarker studies are you intrigued by?

A lot of that [type of research was] presented at the 2024 ASCO Annual Meeting. It’s always valuable because biomarker development has been such a tough space in kidney cancer. When a lot of the early work was done in terms of genomic sequencing and transcriptome analysis, the hope was that we’d find our equivalent of an EGFR mutation, this single gene alteration that if it’s present [indicates that] people will respond [to treatment with an EGFR TKI].

But we’re seeing again and again how difficult that is. That’s going to be the likely case [with] the results of the biomarker analysis from the [phase 3] CLEAR [NCT02811861] and KEYNOTE-426 trials [NCT02853331], which are the frontline immunotherapy/TKI trials. That is not going to be a simple answer.

We think of biomarkers a lot in the metastatic setting, but one area where we need biomarkers is in the adjuvant setting. In the adjuvant setting many patients are cured of their disease by surgery alone. That’s a whole population of patients who are getting no benefit and only potential toxicity from therapy. Can we find better, smarter ways to identify biomarkers for those patients who truly will benefit from adjuvant therapy? There’s been a lot of attempts in this space and there’s still a lot of work to do.

There’s some interesting work coalescing around circulating levels of plasma KIM-1 as potentially a marker of risk of recurrence and potentially even benefit from adjuvant therapy. At the 2024 AACR Annual Meeting an analysis of [the phase 3] CheckMate 914 trial [NCT03138512] showed that perhaps KIM-1 levels were associated with higher degrees of benefit from therapy.

At ASCO 2024 we saw the KIM-1 analysis for [the phase 3] IMmotion010 trial[NCT03024996]. This was an overall negative trial of [Tecentriq] against placebo in the adjuvant setting. But when subsequent analysis looked at patients with high circulating KIM-1 levels versus low circulating KIM-1 levels, the question was: Are we going to see a powerful discrimination where atezolizumab might be beneficial in one group but not the other? That’s something to keep an eye on because that’s such an area of need for biomarker development.

What other trials were you excited to see presented at this year’s ASCO Annual Meeting?

One of the early immunotherapy and TKI regimens was avelumab[Bavencio]plus axitinib [Inlyta]. The [phase 3] JAVELIN Renal 101study [NCT02684006] showed a PFS benefit and a response benefit [with that regimen] but did not have fully mature data to look at OS. [Now] we have our final sense of OS benefits [with that combination].

Looking at rare kidney cancer types is also very important. We know more and more about clear cell, that’s been tremendous and hopefully [that knowledge] will continue to benefit patients in the years to come. But there’s a huge amount of learning that needs to be done on less common kidney cancer types, including non–clear cell and variant histologies. One of the abstracts discussed chromophobe kidney cancer and outcomes with current therapies for this less common kidney cancer subtype.

References

  1. Pal SK, Tran B, Haanen JBAG, et al. CD70-targeted allogeneic CAR T-cell therapy for advanced clear cell renal cell carcinoma. Cancer Discov. 2024;14:1-14. doi:10.1158/2159-8290.CD-24-0102
  2. 2.Srour S, Kotecha R, Curti B, et al. A phase 1 multicenter study (TRAVERSE) evaluating the safety and efficacy of ALLO-316 following conditioning regimen in pts with advanced or metastatic clear cell renal cell carcinoma (ccRCC). Cancer Res. 2023;83(suppl 8):CT011. doi:10.1158/1538-7445.AM2023-CT011
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