Sacituzumab Govitecan Plus Pembrolizumab in the TROPHY-U-01 Trial

Petros Grivas, MD, PhD, Fred Hutchinson Cancer Center at University of Washington, Seattle, discusses the recent results from the phase 2 TROPHY-U-01 study. This trial looked at the combination of sacituzumab govetican, an antibody drug conjugate TROP2 inhibitor, with pembrolizumab, a PD-1 inhibitor, for the treatment of patients with metastatic urothelial carcinoma who had progressed on or after platinum-based chemotherapy.

This study met its primary end point of objective response rate with 41% (20% complete response). Dr Grivas notes that these results support further evaluation of sacituzumab govetican, as well other antibody drug conjugates, in combination with checkpoint inhibition for urothelial carcinoma.

Transcript:

Hello, I'm Dr Petros Grivas, a medical oncologist in Seattle. I'm a professor and the clinical director of the GU cancer program at the University of Washington and Fred Hutchinson Cancer Center. I'm very excited and honored to give you a summary of the recent publication we had in the Journal of Clinical Oncology (JCO) with our colleagues and teams and on behalf of the co-authors. This was Cohort 3 of the TROPHY-U-01 trial, a phase 2 study of sacituzumab govitecan, an antibody drug conjugate against TROP2, plus pembrolizumab, anti-PD–1 in patients with metastatic urothelial carcinoma who had progression after platinum-based chemotherapy.

To add some context, in that particular second-line setting, after progression on platinum-based chemotherapy patients may have a response rate of about 20% with pembrolizumab alone, anti-PD–1 monotherapy. Overall, we know that we need more effective and safe combination therapies. We also know that sacituzumab govitecan by itself, as monotherapy, has a response rate of 28 % in patients with multiple prior lines of therapy. The idea has been to combine the two. There have been data in the lab, translational data supporting the mechanistic rationale of combining the two, suggesting potential additive or synergistic effects in lab models and mechanisms where the TROP1 inhibition, which is the payload for sacituzumab govitecan, can potentially help anti-PD–1 checkpoint inhibition work better.

Based on this strong preclinical data, as well as the clinical data with monotherapy with either compound, either agent, we embarked on this phase 2 trial again in patients with platinum-refractory disease in the second-line space. Those patients received the combination of pembrolizumab plus sacituzumab govitecan. Sacituzumab govitecan was given at the standard dose at 10 mg/kg on day 1 and 8 on a 21-day cycle, the same dose that has been approved as monotherapy in previously treated metastatic urothelial carcinoma. In this particular setting, the patient population consisted of patients who had usually early progression, early resistance to platinum-based chemotherapy and those patients, with a short time to progression on platinum chemotherapy, usually may not do that well with pembrolizumab.

The combination was given to 41 patients and it met the primary end point. The overall response rate from an independent blinded review committee was 41%, again, meeting the primary end point that was based on response rates. About half of those responses were complete responses and the other half were partial responses. And the clinical benefit rate, meaning complete response or partial response or stable disease, was about 46% of patients. About half of patients had clinical benefits. And again, this is a difficult population based on early time to progression on platinum-based chemotherapy that was given before.

The median duration of response was about 11 months and the median time to response was about 1.5 months. So exactly the time it takes to get the first imaging scan. The median progression for survival, 5.3 months, and median overall survival, approximately 13 months. However, I want to caution here that the PFS and OS should be interpreted with a grain of salt because it's a single-arm, not randomized, phase 2 trial. Overall, as I mentioned, the study met the primary efficacy end point.

The toxicity profile was as expected by combining sacituzumab with pembrolizumab, in terms of grade 3 or higher treatment-related adverse events. This happened in about 60% of patients, 3 out of 5, and the most common grade 3 or higher treatment-related adverse events were neutropenia, about 10 % had febrile neutropenia, and diarrhea, about 20% had diarrhea, grade 3 or higher, and about 15% of patients had to stop treatment because of toxicity. Systemic steroids were used in a small proportion of patients as expected with pembrolizumab alone. And growth factor (G-FCSF) was given about a third of the patients. And again, the growth factor is very important when we give Sacituzumab govitecan because we want to prevent neutropenia and growth factor, G-CSF can be used and should be used in my opinion as primary prophylaxis.

Going forward, of course, we're very excited about the results of the study. And we're translating this phase 2 positive trial results to a newly designed phase 3 randomized clinical trial that will run through the NCTN cooperative groups. This trial is going to be compare the combination of sacituzumab govitecan plus pembrolizumab, as combination, vs sacituzumab govitecan alone, as monotherapy. This will be in patients with prior immunotherapy and progression of disease, and that trial will allow prior chemotherapy, will allow prior enfortumab vedotin. As I mentioned, that trial will compare sacituzumab govitecan plus pembrolizumab vs sacituzumab govitecan alone, mainly to answer the question, do we need to re-challenge patients with checkpoint inhibition if they had prior exposure to that? It will be a very important phase 3 trial and it's being designed by ECOG-ACRIN and will be called ECOC-ACRIN 8231 and we're very excited about the design and  launch in the near future.

Overall, I would say that the combination of antibody drug conjugates and checkpoint inhibition has been very promising. In addition to the results of this study, we have seen a really impressive and exciting transformative results with a combination of enfortumab vedotin, antibody drug conjugate against NECTIN-4, and pembrolizumab, anti-PD–1 in the frontline setting. And we saw that in the data from EV-103 and EV-302. And EV-302 was presented at the ESMO and ASCO GU recently, and these results led to the FDA approval of pembrolizumab and enfortumab vedotin in the front-line setting of metastatic urothelial carcinoma. So very excited about the combination of antibody drug conjugates plus checkpoint inhibition. I think there's a lot of attention in the field, and many more trials being designed. I'm optimistic that in the future, we will be able to evaluate further combinations, aiming to help our patients in living longer, living better, and changing even further the treatment landscape of this disease and moving the needle forward in terms of prolonged life and higher quality of life.

Very excited about what is happening in the field and the new developments of many, many trials and looking forward for further biomarker work, further attempts for a precision and personalized oncology in the future. Thank you so much and have a great day.

Source:

Grivas P, Pouessel D, Park CH, et al. Sacituzumab govitecan in combination with pembrolizumab for patients with metastatic urothelial cancer that progressed after platinum-based chemotherapy: TROPHY-U-01 cohort. J Clin Oncol. Published on January 23, 2024. doi:10.1200/JCO.22.02835