Patients with sarcomatoid and/or rhabdoid (S/R) metastatic non-clear cell renal cell carcinoma (nccRCC) are known to have poor clinical outcomes. Now, a study conducted by the International Metastatic RCC Database Consortium (IMDC) aimed to assess the potential benefits of immunotherapy (IO)-based regimens in this patient population.
Previous trials have shown that IO-based combination therapies have demonstrated significant efficacy in patients with metastatic S/R clear cell RCC compared to VEGF-targeted therapy (VEGF-TT). Additionally, there have been promising results indicating the activity of IO-based regimens in patients with advanced nccRCC. Therefore, researchers sought to evaluate the effectiveness of IO regimens specifically in patients with S/R nccRCC.
The study presented at the 2023 ASCO Annual Meeting included patients with advanced nccRCC who were treated with first-line IO regimens (IO/IO or IO/VEGF-TT) or first-line VEGF-TT monotherapy (sunitinib or pazopanib) (Abstract 4519). The cases were categorized as either S/R or non-S/R, and the primary outcomes assessed were overall survival (OS) and time-to-treatment failure (TTF) in patients with S/R nccRCC receiving first-line IO or VEGF-TT. The overall response rate (ORR) was a secondary outcome. Cox regression models adjusted for age, IMDC risk groups, and nccRCC subtype were used to compare OS and TTF between the groups (IO vs. VEGF-TT), while logistic regression was used to compare ORR between the groups.
The study enrolled a total of 103 patients diagnosed with S/R nccRCC, out of which 33 patients (32%) were administered first-line IO regimens. The patients were followed for a median duration of 31 months. After considering various factors that could affect the outcomes, it was observed that patients with S/R nccRCC who received IO regimens exhibited significantly improved survival outcomes compared to those who received VEGF-TT. The median overall survival (mOS) for patients on IO regimens was not reached, while it was 7.1 months for those on VEGF-TT. Similarly, the median time-to-treatment failure (mTTF) was 9.4 months for IO regimens and 2.9 months for VEGF-TT.
Furthermore, patients with S/R nccRCC who underwent IO regimens showed a higher overall response rate (ORR) of 34.1 percent, whereas the ORR for those on VEGF-TT was 10.9 percent. On the other hand, among the 430 patients with non-S/R nccRCC, including 44 on IO regimens, there were no significant differences in survival outcomes between the two treatment groups. The mOS was 24.4 months for IO regimens and 14.8 months for VEGF-TT, while the mTTF was 4.2 months for IO regimens and 5.0 months for VEGF-TT.
For a deeper understanding of the study, Oncology Times chatted with first author, Chris Labaki, MD, a postdoctoral research fellow at The Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard.
Oncology Times: Were there any significant differences observed in the treatment response or survival outcomes between patients with sarcomatoid and rhabdoid subtypes of nccRCC?
Labaki: "Based on our current work, patients with metastatic S/R nccRCC appear to substantially benefit from immunotherapy-based regimens as compared to targeted therapies (i.e., VEGF tyrosine kinase inhibitors [VEGF TKIs]). This is consistently seen across the different outcomes evaluated, including the co-primary outcomes of OS and progression-free survival (PFS), as well as the secondary outcome of ORR, notably after controlling for potential confounding factors (including age, nccRCC subtype, and IMDC risk groups).
"For instance, we identify a median PFS of 9.4 months (95% CI: 2.7-NR) among patients with S/R nccRCC treated with immunotherapy-based regimens, as compared to 2.9 months (95% CI: 2.2-4.3) among similar patients treated with VEGF TKIs, with a hazard ratio of 0.34 (95% CI: 0.21-0.59). Similarly, we identify a hazard ratio of 0.25 (95% CI: 0.13-0.49) for OS, further illustrating the large benefit derived from immunotherapy-based regimens among this patient subgroup.
"Regarding ORR, patients with S/R nccRCC receiving immunotherapy-based regimens presented with an ORR of 34.5 percent, as opposed to 10.9 percent among those treated with VEGF TKIs (P=0.006). Based on these results, patients with S/R nccRCC show substantial benefit and highly promising responses when receiving immunotherapy-based regimens in the first-line setting, consisting of dual checkpoint inhibition or an immune checkpoint inhibitor combined with targeted therapies."
Oncology Times: Were there any notable safety concerns or adverse events associated with the use of immunotherapy-based regimens?
Labaki: "The current work aimed to assess the efficacy of immunotherapy-based regimens among patients with metastatic S/R nccRCC. Specifically, the primary and secondary outcomes of the current study related to overall survival, progression-free survival, and the overall response rate. Nonetheless, treatment safety represents an important factor that is definitely to be taken into consideration in the management of patients with metastatic RCC. Specifically, the safety profile of immunotherapy-based regimens among patients with metastatic S/R nccRCC is currently undergoing and will be reported in future research efforts."
Oncology Times: What are the potential implications of these findings for clinical practice and are there any future research directions to be pursued based on these results?
Labaki: "The current findings are highly promising and show a large benefit to IO-based regimens among patients with S/R nccRCC in a rigorous statistical design controlling for potential confounding factors. Although conducting prospective trials in patients with S/R nccRCC would be challenging, given the small number of patients presenting with this disease subtype, it would be important to validate these findings in a prospective trial. Additional retrospective analyses could also be informative, helping to further confirm the benefit of IO-based regimens in these patients."
Dibash Kumar Das is a contributing writer.