AMBASSADOR Study Findings and Adjuvant Treatment for Urothelial Carcinoma

A roundtable discussion, moderated by Vadim Koshkin, MD, discussed the post-EV-302 world for metastatic urothelial carcinoma, as well as recent trial data from the American Society of Clinical Oncology Genitourinary Cancers Symposium 2024. Dr. Koshkin was joined by Petros Grivas, MD, PhD; Karine Tawagi, MD; Terence Friedlander, MD; and Guru Sonpavde, MD.

In the fourth segment of the roundtable series, the panel transitioned to the AMBASSADOR Alliance A031501 trial findings and other adjuvant treatment considerations for urothelial carcinoma.

Watch the next segment in this series.

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Dr. Koshkin: You mentioned adjuvant therapy here, and adjuvant immunotherapy in particular, which I think is a great segue into one of our next topics. Some of the most compelling data in urothelial cancer was actually presented at this meeting, specifically the AMBASSADOR study.

Dr. Sonpavde: The AMBASSADOR trial is a phase 3 trial comparing adjuvant pembrolizumab versus observation. It was not placebo-controlled with core primary endpoints of disease-free survival (DFS) and overall survival (OS). This is exactly the same population as the CheckMate 274 trial, comprising high-risk muscle-invasive disease with or without neoadjuvant chemo. If neoadjuvant chemo was administered, patients could be T2 or higher. Without neoadjuvant chemo, patients had to be T3 or higher. In this study, unlike CheckMate 274, which focused on PD-L1 high and intention to treat populations, the co-primary endpoints were DFS and OS.

As we speak, this study is being reported. The abstract shows that one of the co-primary endpoints, DFS, was met. The median DFS increased from around 14 months to 29 months. I would say it’s in the same ballpark as the CheckMate 274 data. So, it is encouraging to see, but we need to wait and see what the rest of the endpoints look like.

Dr. Grivas: I find it interesting, as Dr. Sonpavde mentioned, that we see at least a replication of the positive signal in a trial that uses an anti-PD-1 versus observation. Before this trial, there was a tie between atezolizumab versus observation in the larger IMvigor010 trial and CheckMate 274. There was some discussion about the performance of the control arm, which was notably different. The median DFS of the placebo arm in CheckMate 274 was only about 11 months, whereas in the observation arm of the atezo trial, it was higher at 16.6 months. So, this trial, the AMBASSADOR trial, serves as a tiebreaker.

Dr. Friedlander: I agree. It supports the use of adjuvant immunotherapy to prevent relapses. However, we do not have overall survival data from any study in the adjuvant setting. This raises the question of whether we are just treating patients with immunosensitive disease earlier. Waiting for relapse can lead to rapid progression, brain metastases, pulmonary embolism, and increased morbidity and mortality. Treating in the adjuvant setting makes sense. If faced with a choice between adjuvant nivolumab or adjuvant pembrolizumab for a patient, I wonder how one would decide. Would you flip a coin?

Dr. Koshkin: These cross-trial comparisons are always tricky, especially when the numbers look similar and the hazard ratios are essentially identical. I do not think these numbers alone will help us decide between pembrolizumab and nivolumab.

Dr. Grivas: I agree. It is challenging to compare across trials. Pembrolizumab and nivolumab have similar mechanisms of action, and currently, nivolumab has FDA approval. We need to wait and see what happens with pembrolizumab. It will also be important to review the full manuscript to understand population characteristics and differences in how disease-free survival is defined. For now, the data looks comparable in terms of hazard ratio.

Dr. Tawagi: Indeed. Another question that arises is what to do for patients who progress on adjuvant immunotherapy?

Dr. Friedlander: Would you consider EV/pembro for those patients?

Dr. Tawagi: Personally, I would consider it at this point, although it is not based on any data.

Dr. Koshkin: It also depends on when the progression happens, right?

Dr. Tawagi: Exactly. How soon is it happening?

Dr. Sonpavde: I agree. I would consider EV/pembro for patients who progress on adjuvant therapy. There seems to be a special interaction between EV and pembrolizumab that might offer synergistic benefits. While the textbook approach might be to use EV alone, I would not want to deny a patient the potential synergistic effect.

Dr. Koshkin: Let me ask you to elaborate. If a patient on adjuvant pembrolizumab is actively progressing, would you add EV and continue pembrolizumab?

Dr. Sonpavde: I would continue pembrolizumab with EV rather than stop pembrolizumab.

Dr. Friedlander: There is preclinical evidence suggesting immunogenic cell death with MMA-containing antibody-drug conjugates. This releases various immunologic mediators or signals, attracting immune cells. That was the rationale for combining immunotherapy with EV. However, we have not proven that is what happens clinically. Until we have better data, continuing both treatments to generate a durable immune response makes sense.

Dr. Grivas: This underscores the importance of phase 3 trials like ECOG-ACRIN 8231, which will hopefully provide more clarity on the best approach for these patients.

Dr. Koshkin: Absolutely, it’s a complex question with no clear answer at the moment.