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New treatments for renal cell carcinoma (RCC) have primarily benefited patients with the most common histology, clear cell (cc), but the treatments have not been as successful in the 25% of patients with variant histology.

"Intriguingly, these approved agents have been developed and received approval on the basis of their activity in ccRCC, yet have historically been used in a histology-agnostic fashion for the treatment of non-ccRCC as well, with only limited success," said Nazli Dizman, MD, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues.

These efforts have coalesced into meaningful improvements in clinical outcomes for patients diagnosed with non-ccRCCs, the team wrote in a review in the .

Dizman and co-author Nicholas Salgia, an MD/PhD student at Roswell Park Comprehensive Cancer Institute and the University of Buffalo Jacobs School of Medicine and Biomedical Sciences in New York, discussed some of the ongoing research in the following interview.

The most common variant histology, papillary RCC (pRCC), has been associated with MET hyperactivity. Please tell us about one of the most notable recent trials exploring MET-directed therapy for these patients.

Dizman and Salgia: The exploration of MET-directed therapies in patients with papillary RCC (pRCC) has seen incredibly exciting progress over the past few years. In particular, the is among the most important recent studies. PAPMET randomized patients with pRCC to receive either sunitinib (a VEGF-directed receptor tyrosine kinase inhibitor) or one of three different MET inhibitors: cabozantinib [Cabometyx], crizotinib [Xalkori], and savolitinib [Orpathys]. The crizotinib and savolitinib arms were closed to accrual following an interim analysis, resulting in a head-to-head comparison of cabozantinib with sunitinib.

In total, 44 patients were randomized to receive cabozantinib and 46 received sunitinib. The median progression-free survival with cabozantinib was 9.0 months, outperforming sunitinib (5.6 months, P=0.019).

To date, PAPMET remains the only randomized trial to show a survival benefit with MET inhibition in patients with pRCC, thus promoting cabozantinib as a standard-of-care option and additionally serving as a crucial foundation for ongoing investigations combining MET inhibitors with immune checkpoint inhibitor (ICI) agents.

What combination therapies are being explored for patients with pRCC?

Dizman and Salgia: Numerous studies are currently enrolling patients to explore the combination of MET inhibitors with ICIs targeting the PD-1/PD-L1 axis. Building off the aforementioned PAPMET study, PAPMET2 (SWOG 2200; ) is comparing cabozantinib monotherapy with a combination of cabozantinib with atezolizumab [Tecentriq] for patients with pRCC who have received 0-1 previous lines of therapy.

Additionally, the STELLAR-304 trial () is assessing the combination of zanzalintinib (a next-generation MET-tyrosine kinase inhibitor) with nivolumab compared with sunitinib, while the SAMETA trial () is a 3-arm study comparing (1) the combination of anti-MET savolitinib plus durvalumab (anti-PD-1) against either (2) sunitinib or (3) durvalumab alone.

These three trials represent some of the most promising investigations into combining MET inhibition with immuno-oncology strategies.

Recent subgroup analyses of trials with ICIs suggest that patients with sarcomatoid RCC respond preferentially to them. Can you tell us about one of these subgroup analyses?

Dizman and Salgia: The first major phase III trial investigating front-line ICIs in patients with metastatic renal cell carcinoma was comparing nivolumab plus ipilimumab with sunitinib. While survival benefits with nivolumab/ipilimumab were seen across the board in this study, the sarcomatoid RCC subgroup was among the most successful populations in terms of immunotherapy responsiveness.

Among , the objective response rate to nivolumab/ipilimumab was 60.8% compared with only 23.1% with sunitinib, and significant improvements in both progression-free survival and overall survival were achieved with nivolumab/ipilimumab (HR 0.50 and 0.46, respectively). Most strikingly, in the sarcomatoid RCC subgroup, 23% of patients experienced a complete response with nivolumab/ipilimumab compared with only 6% of patients who received sunitinib.

Similar results have consistently been demonstrated in numerous other subgroup analyses of sarcomatoid RCC patients within randomized phase III trials in RCC, providing an exciting advancement in the clinical management of patients diagnosed with this historically aggressive disease.

What has been discovered about the biological mechanisms that underlie the responsiveness of sarcomatoid RCC to ICIs?

Dizman and Salgia: Recent work has relied on transcriptomic, proteomic, and more recently, epigenomic approaches to interrogate the unique properties of sarcomatoid RCC tumors underlying their responsiveness to ICI.

from the IMmotion151 trial population demonstrated that sarcomatoid RCC tumors had a higher prevalence of PD-L1 positivity and enrichment of immunogenic and inflammatory gene programs, including effector T cell and myeloid inflammation profiles. This analysis also revealed increased interferon-associated signaling in sarcomatoid RCC. These findings were in further studies utilizing additional large patient cohorts.

Intriguingly, however, PD-L1 status has not been predictive of response to ICIs in RCC, unlike in other solid tumors, and the predictive utility of these inflammatory gene signatures enriched in sarcomatoid RCC also remain inconclusive in the RCC population at large. Intriguing work that has just been published has also revealed that at the H3K27 locus, which results in upregulation immune activation and effector responses.

Together, these findings represent critical advances in the field's understanding of sarcomatoid RCC biology and resultant immune responsiveness, but still lack mechanistic rigor, reinforcing the pressing need to continue studies into this tumor type.

Is there an ongoing trial of patients with variant histology you are especially looking forward to seeing the results of?

Dizman and Salgia: The clinical science surrounding variant histology RCCs is rapidly evolving and has resulted in numerous exciting studies that we hope to hear results from in the very near future.

The stands among the most fascinating, in part because it employs cabozantinib as a standard-of-care control. As previously noted, cabozantinib resulted in improved survival outcomes for patients with papillary RCC relative to sunitinib in the PAPMET trial, resulting in cabozantinib being the only agent to have demonstrated improved efficacy relative to VEGF-directed agents through a randomized controlled trial.

The combination of cabozantinib with atezolizumab has already shown promising results in patients with variant histology RCCs within the , with an objective response rate of 32% and disease control rate of 94%, alongside a median progression-free survival of 9.3 months. Given the robust early-phase clinical data supporting this combination and the positive results of the initial PAPMET trial, PAPMET2 is absolutely a trial to keep an eye on in this space.

Please tell us about any research in this area that you have been involved in.

Dizman and Salgia: Our group at Roswell Park Comprehensive Cancer Center has taken a keen interest in better understanding the paradoxical biology of sarcomatoid RCC, undertaking efforts to marry the clinical aggressiveness of the tumor type with its responsiveness to immune checkpoint inhibitors.

We recently published a demonstrating that the abundance of sarcomatoid features in RCC tumors carries prognostic implications, and further associates with differential biological properties. Historically, sarcomatoid RCC is a dichotomous diagnosis, defined by either the presence or absence of sarcomatoid features. We demonstrated that increased sarcomatoid feature abundance was associated with worse survival outcomes and more aggressive transcriptomic features.

We are additionally employing multiple high-dimensional strategies to better understand the processes of sarcomatoid transformation and resultant immune activity through comprehensive interrogations of tumor-immune interactions in the tumor microenvironment.

Stay tuned for forthcoming publications detailing these works!

Read the review here.