Urothelial Carcinoma at ESMO: THOR, DAD, and Other Trials of Note

Live from the ESMO Congress 2023, Brad McGregor, MD, Dana-Farber Cancer Institute, and Guru P. Sonpavde, MD, AdventHealth Cancer Institute, highlight the Double Antibody Drug conjugate trial, a pooled analysis for the correlation of safety and efficacy associated with atezolizumab in different solid tumors, and other bladder cancer-related studies or datasets that have their attention.

What was the Double Antibody Drug (DAD) conjugate trial of SG plus EV? Can you share the inspiration, design, findings, and larger implications of the study?

Dr. McGregor: The DAD conjugate trial was a novel concept that Dr. Sonpavde and I developed together while he was still at Dana-Farber. The idea behind this trial was to explore the combination of antibody-drug conjugates (ADCs) with unique delivery mechanisms, specifically enfortumab vedotin (EV) and sacituzumab govitecan (SG). These two ADCs target different antigens and use different payloads, resulting in distinct toxicity profiles. Even though these agents are used sequentially in urothelial carcinoma, we wondered why we could not combine them simultaneously.

The phase 1 trial aimed to establish the maximum tolerated dose of both drugs while monitoring dose-limiting toxicities during the first cycle. The study enrolled 24 patients, ranging in age from 70 to 88, and we found that the maximum tolerated dose was the full dose of SG (10 mg/kg) in combination with the full dose of EV (1.25 mg/kg) on days 1 and 8 of a 21-day cycle. While there were some dose-limiting toxicities and risks, the combination showed promise. The trial demonstrated a 70% objective response rate, including 3 complete responses among 23 patients. Importantly, 9 of these patients maintained responses for at least 15 months, indicating potential durability. This is the first study to combine 2 ADCs simultaneously, and it could have implications for other malignancies beyond bladder cancer.

Dr. Sonpavde: To add to that, the rationale for this trial was grounded in the fact that EV and SG target different surface antigens and employ distinct payloads. Additionally, both agents have single-agent activity in urothelial carcinoma, making them compelling candidates for combination therapy. The findings showed that the combination of SG and EV was well-tolerated at the maximum tolerated dose, and the response rates were quite promising. The addition of pembrolizumab to this combination in future studies holds even more exciting prospects for advancing patient care.

Can you tell us about pooled analysis for the correlation of safety and efficacy associated with atezolizumab in different solid tumors?

Dr. Sonpavde: This analysis involved a large retrospective study that examined the correlation between safety and efficacy of atezolizumab, a PD-L1 inhibitor, in various solid tumors. The study included data from 14 clinical trials encompassing over 9,500 patients.

The primary objective of the analysis was to investigate whether the grade of immune-related adverse events (irAEs) correlated with outcomes. One hypothesis was that more severe irAEs might be associated with better survival, as they indicate T-cell activation. Conversely, milder irAEs might allow patients to continue treatment without interruption.

The findings revealed that grade 1 and 2 irAEs were associated with improved survival, with a hazard ratio of 0.65. On the other hand, severe irAEs (grade 3 or 4) were not linked to better survival, and there was a trend towards worse survival with a hazard ratio of 1.16 (P=.06).

These results emphasize the significance of the grade of irAEs in predicting outcomes among patients receiving atezolizumab. It highlights the importance of distinguishing between the severity of these events, as it can influence patient management and treatment decisions.

The interplay between treatment activity and toxicity is still a complex area that needs further research. Understanding the potential correlation between irAEs and survival can help in identifying patients who might derive greater benefits from immune checkpoint inhibitors.

What other urothelial carcinoma-related studies or datasets have your eye at this year’s meeting?

Dr. McGregor: I would like to highlight a poster that I had the privilege to work on, along with Dr. Sonpavde and others. It addresses an unmet need in urothelial carcinoma. Most clinical trials and studies, like the ones discussing EV pembrolizumab and cis-gem nivolumab (Nivo), tend to exclude patients with predominant variant histology, such as small cell or sarcomatoid features. These patients with unique histologies often face uncertainty about the most suitable treatment approaches.

In response to this challenge, we developed a rare geospatial protocol aimed at investigating the use of Nivo in combination with ipilimumab (IPI) for variant histologies. We enrolled 19 patients in the initial phase and observed a promising 39% objective response rate, which was quite exciting compared to the results of Nivo/IPI in the typical urothelial carcinoma.

This led to an expansion of the study, and we ultimately enrolled 50 patients who had progressed on prior lines of therapy. The patient population included those with adenocarcinoma, small cell carcinoma, and urothelial carcinoma with variant features. Notably, we observed a 37% objective response rate in the expanded cohort, with small cell carcinoma patients achieving a remarkable 50% objective response rate, which appeared to be quite durable. Importantly, we did not identify any new toxicity signals.

While the sample size remains relatively small, 50 patients is significant for this rare variant of bladder cancer. We are hopeful that as we continue to gather more data and delve into genomics and PD-L1 expression, this research will pave the way for changes in the management of patients with variant histologies.

Dr. Sonpavde: One urothelial carcinoma-related study I would like to highlight is the phase 3 trial that compared erdafitinib and pembrolizumab in patients with advanced urothelial carcinoma in the second-line setting after chemotherapy. Erdafitinib targets FGFR3 and FGFR2 activating mutations and fusions, which are relevant in some urothelial carcinoma cases.

The intriguing finding in this study was that while overall survival outcomes were similar for pembrolizumab and erdafitinib, the latter demonstrated a higher response rate, consistently around 45% as seen in previous studies. Pembrolizumab, on the other hand, showed activity in this population, with a response rate of 21%. Notably, this response rate was similar to what has been observed with pembrolizumab in the intention-to-treat, all-comer population.

The implications of this study may not be particularly relevant today because pembrolizumab is now often used in the first-line setting in combination with EV, and Nivo has moved forward in the first-line setting with gem-cis in the CheckMate 901 trial. Therefore, the situation where one must choose between erdafitinib and pembrolizumab as salvage treatments may be less common.

However, if faced with this choice, both options seem reasonable based on the data, considering their comparable survival outcomes. The decision could be influenced by the patient’s symptoms, as erdafitinib, with its higher response rate, might be preferred in more symptomatic patients. Conversely, pembrolizumab is a reasonable choice in less symptomatic patients, given its similar survival outcomes. Additionally, it is crucial to consider the different toxicities associated with these agents and have a comprehensive discussion with the patient before making a treatment choice.

In summary, both erdafitinib and pembrolizumab can be considered as salvage treatments in these patients, and the decision-making process should be patient-centered.

View their previous remarks on EV-302 and CheckMate 901.