New treatment methods for renal cell carcinoma (RCC) have primarily benefited patients with the most common histology, clear cell carcinoma (cc). However, the treatments were not as successful in the 25% of patients with different histology.
“Interestingly, these approved agents were developed and approved based on their activity in ccRCC, although they have also been used in the past in a histology-agnostic manner to treat non-ccRCC with only limited success,” said Dr. Nazli Dizman of the University of Texas MD Anderson Cancer Center in Houston and colleagues.
These efforts have led to significant improvements in clinical outcomes for patients with non-ccRCCs, the team wrote in a review in the ASCO Textbook.
Dizman and co-author Nicholas Salgia, an MD/PhD student at the Roswell Park Comprehensive Cancer Institute and the University of Buffalo Jacobs School of Medicine and Biomedical Sciences in New York, discuss some of the ongoing research in the following interview.
The most common variant of histology, papillary renal cell carcinoma (pRCC), is associated with MET Hyperactivity. Please tell us about one of the most remarkable studies of recent times in which MET-targeted therapy for these patients.
Dizman and Salgia: The research of MET-targeted therapies in patients with papillary renal cell cancer (pRCC) have made incredibly exciting progress in recent years. In particular, the PAPMET trial is one of the most important current trials. PAPMET randomized patients with pRCC to receive either sunitinib (a VEGF-targeted 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 for accrual after an interim analysis, resulting in a direct comparison of cabozantinib to sunitinib.
A total of 44 patients were randomized to receive cabozantinib and 46 to receive sunitinib. The median progression-free survival with cabozantinib was 9.0 months, which was better than with sunitinib (5.6 months, P=0.019).
To date, PAPMET is the only randomized trial demonstrating a survival benefit from MET inhibition in patients with pRCC, promoting cabozantinib as a standard of care and providing an important foundation for ongoing trials combining MET inhibitors with immune checkpoint inhibitors (ICI).
What combination therapies are being researched for patients with pRCC?
Dizman and Salgia: Numerous trials are currently recruiting patients to investigate the combination of MET inhibitors with ICIs targeting the PD-1/PD-L1 axis. Building on the above-mentioned PAPMET trial, PAPMET2 (SWOG 2200; NCT05411081) compares cabozantinib monotherapy with a combination of cabozantinib and atezolizumab (Tecentriq) for patients with pRCC who have received 0-1 prior lines of therapy.
In addition, the STELLAR-304 trial (NCT05678673) is investigating the combination of zanzalintinib (a next-generation MET tyrosine kinase inhibitor) with nivolumab compared with sunitinib, while the SAMETA trial (NCT05043090) is a three-arm trial comparing (1) the combination of anti-MET savolitinib plus durvalumab (anti-PD-1) with either (2) sunitinib or (3) durvalumab alone.
These three studies are among the most promising investigations into the combination of MET inhibition with immuno-oncology strategies.
Recent subgroup analyses of ICI trials suggest that patients with sarcomatoid renal cell carcinoma (RCC) respond preferentially to them. Can you tell us about one of these subgroup analyses?
Dizman and Salgia: The first large Phase III trial to evaluate first-line ICIs in patients with metastatic renal cell carcinoma was CheckMate 214, which compared nivolumab plus ipilimumab with sunitinib. While survival benefits were consistently observed with nivolumab/ipilimumab in this trial, the subgroup of sarcomatoid renal cell carcinoma was one of the most successful populations in terms of response to immunotherapy.
In 139 patients with sarcomatoid features, the objective response rate to nivolumab/ipilimumab was 60.8% compared to only 23.1% with sunitinib, and both progression-free survival and overall survival were significantly improved with nivolumab/ipilimumab (HR 0.50 and 0.46, respectively). Most strikingly, in the subgroup of sarcomatoid renal cell carcinoma, 23% of patients with nivolumab/ipilimumab had a complete response compared to only 6% of patients receiving sunitinib.
Numerous other subgroup analyses of patients with sarcomatoid RCC in randomized phase III RCC trials have consistently shown similar results, representing an important advance in the clinical treatment of patients with this historically aggressive disease.
What has been discovered about the biological mechanisms underlying the response of sarcomatoid renal cell carcinoma to ICIs?
Dizman and Salgia: Recent work has used transcriptomic, proteomic and, more recently, epigenomic approaches to investigate the unique properties of sarcomatoid RCC tumors that underlie their response to ICI.
A correlative analysis of the IMmotion151 study population showed that sarcomatoid renal cell carcinomas had a higher prevalence of PD-L1 positivity and an enrichment of immunogenic and inflammatory gene programs, including effector T cells and myeloid inflammatory profiles. This analysis also revealed increased interferon-associated signaling in sarcomatoid renal cell carcinomas. These results were confirmed in further studies with additional large patient cohorts.
Interestingly, however, unlike other solid tumors, PD-L1 status was not a predictor of response to ICIs in RCC, and the predictive utility of these inflammatory gene signatures enriched in sarcomatoid RCC is also equivocal in the RCC population as a whole. Interesting, just published work has also shown that sarcomatoid RCC tumors exhibit unique acetylation events at the H3K27 locus, leading to upregulation of immune activation and effector responses.
Taken together, these findings represent a crucial advance in understanding the biology of sarcomatoid renal cell carcinoma and the resulting immune response. However, they still lack mechanistic rigor, highlighting the urgent need for further studies on this tumor type.
Is there an ongoing study involving patients with abnormal histology whose results you are particularly excited about?
Dizman and Salgia: The clinical science surrounding variant histology renal cell cancer is evolving rapidly and has resulted in numerous exciting studies from which we hope to see results in the near future.
The PAPMET2 trial is one of the most intriguing, in part because it uses cabozantinib as standard therapy. As mentioned above, in the PAPMET trial, cabozantinib led to improved survival outcomes in patients with papillary renal cell cancer compared to sunitinib. This makes cabozantinib the only agent that has shown improved efficacy compared to VEGF-targeted agents in a randomized, controlled trial.
The combination of cabozantinib with atezolizumab has already shown promising results in the Phase Ib COSMIC-021 trial in patients with RCCs with variant histology, with an objective response rate of 32% and a disease control rate of 94%, as well as a median progression-free survival of 9.3 months. Given the solid early phase clinical data supporting this combination and the positive results from the first PAPMET trial, PAPMET2 is definitely a trial to keep an eye on in this space.
Please tell us about any research you have been involved in in this area.
Dizman and Salgia: Our group at Roswell Park Comprehensive Cancer Center has a keen interest in better understanding the paradoxical biology of sarcomatoid renal cell cancer and is attempting to reconcile the clinical aggressiveness of this tumor type with its response to immune checkpoint inhibitors.
We recently published a report showing that the frequency of sarcomatoid features in renal cell carcinoma has prognostic implications and is furthermore associated with distinct biological characteristics. Historically, sarcomatoid renal cell carcinoma is a dichotomous diagnosis defined by either the presence or absence of sarcomatoid features. We have shown that an increased frequency of sarcomatoid features is associated with worse survival outcomes and more aggressive transcriptomic features.
Furthermore, we employ several high-dimensional strategies to better understand the processes of sarcomatoid transformation and the resulting immune activity by comprehensively studying tumor-immune interactions in the tumor microenvironment.
Stay tuned for upcoming releases with details on these works!
Read the review here.
Dizman reported equity and other ownership interests in several pharmaceutical companies and consulting work for Vivreon Biosciences.
Salgia reported no conflicts of interest.
