Sacituzumab Govitecan/Enfortumab Vedotin ± Pembrolizumab Under Investigation in Metastatic Urothelial Carcinoma

Based on the early efficacy and safety data derived from the phase 1 DAD trial (NCT04724018) investigating the combination of sacituzumab govitecan-hziy (Trodelvy) and enfortumab vedotin-ejfv (Padcev) in patients with locally advanced or metastatic urothelial carcinoma who progressed on platinum-based chemotherapy and immunotherapy, or who progressed on 1 prior line of therapy and were ineligible for cisplatin, the study will expand to include more patients, according to Bradley McGregor, MD.¹

Additionally, the DAD-IO expansion of the study will investigate the addition of pembrolizumab (Keytruda) to sacituzumab govitecan plus enfortumab vedotin in patients with treatment-naive metastatic urothelial carcinoma.

Initial results from the DAD trial demonstrated that evaluable pretreated patients (n = 23) treated with sacituzumab govitecan plus enfortumab vedotin experienced an overall response rate (ORR) of 70% (95% CI, 47%-87%), including 3 patients who had a complete response. This regimen was well tolerated, and the maximum tolerated dose (MTD) was established as the full standard dose of both drugs.²

The DAD study will continue to explore this combination in previously treated patients, and DAD-IO will extend to treatment-naive patients, adding pembrolizumab to the regimen. Both arms aim to enroll 41 patients each.¹ 

“[DAD-IO] has gone through the process with the institutional review board and is ready to activate and start enrolling patients,” McGregor said in an interview with OncLive^®. McGregor is a senior physician, clinical director of the Lank Center for Genitourinary Oncology, and the Marra Lochiatto Investigator at the Dana-Farber Cancer Institute, and assistant professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

In the interview, McGregor explained the rationale for combining sacituzumab govitecan and enfortumab vedotin in the treatment of patients with advanced urothelial carcinoma; expanded on prior data for the combination of the 2 antibody-drug conjugates (ADCs); and detailed the goals of adding pembrolizumab to this regimen in the treatment-naive setting.

OncLive: What are some of the biggest unmet needs for patients with metastatic urothelial carcinoma?

McGregor: The advances we have made [in metastatic urothelial carcinoma] in the past couple of years have been extraordinary. We saw data presented at the 2023 ESMO Congress for the combination of enfortumab vedotin and pembrolizumab [in the frontline setting showing] an unprecedented survival rate and an ORR that were improved vs platinum-based chemotherapy.

However, we can always do better. We're always hoping for more for our patients. To get a [high] response rate is great; we want 100%. We're looking at how we can build upon the activity we see with the combination of enfortumab vedotin and pembrolizumab.

What was the initial rationale for the DAD trial?

When we think about urothelial carcinoma, we know that ADCs play a critical role in the management [of this disease]. Enfortumab vedotin [monotherapy] is [approved] in the United States in the second-line setting based on [data from] the phase 3 EV-301 trial [NCT03474107] showing improvement vs chemotherapy in the post-platinum and post–immuno-oncology [IO] setting.

Sacituzumab govitecan was granted accelerated approval [for patients with locally advanced or metastatic urothelial cancer who previously received a platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor], based on activity in the phase 2 [TROPHY-U-01] trial [NCT03547973].

Both these ADCs are available in the United States; they have unique toxicities, different payloads, and different targets. We combine chemotherapy regimens together often, and this is the basis for multi-agent chemotherapy. However, prior to our data, no trial looked at combining 2 different ADCs to be given simultaneously in any cancer. Therefore, given this idea that we have different targets, different payloads, and non-overlapping toxicities, there's a rational idea that these drugs could be combined. That was the basis for the DAD trial that we presented at 2023 ESMO Congress.

What were the key findings previously reported from the DAD study?

DAD showed that these drugs could be given safely together. We had 23 patients with a median of 70 years of age. Only one patient [had previously] progressed on IO alone; most patient had previously received both platinum and IO. [This study used] a Bayesian optimal interval design, and what we showed was that the combination of enfortumab vedotin and sacituzumab govitecan can be given safely. The MTD was full-dose sacituzumab govitecan at 10 mg/kg with full-dose enfortumab vedotin at 1.25 mg/kg on days 1 and 8 of each 21-day cycle.

However, given cumulative toxicity concerns, [the MTD] was not the dose recommended to go forward. That dose recommendation is made with a caveat that granulocyte–colony stimulating factor [G-CSF] was given to most patients. In the first 6 patients [treated], there were 2 episodes of neutropenic fever; subsequently, we allowed G-CSF to be given at investor discretion per ASCO guidelines. Sixteen of the following 17 patients did receive G-CSF with cycle 1.

When we combined these drugs with G-CSF, it was very well tolerated with no synergistic toxicity signals. Equally encouraging, we had a 70% ORR in the post-platinum and -IO setting, which is far [higher] than you would see with either drug alone.

What is the goal of the continued DAD study and the expansion into the DAD-IO trial?

Given that exciting data, we want to see if [this ORR] is real. Twenty-three patients are a small number. That is the basis for the expansion of the DAD trial, looking to validate this data in the post-platinum and -IO setting with an additional 40 patients. However, as we alluded to with enfortumab vedotin plus pembrolizumab now a standard of care [in the frontline metastatic setting], how can we build upon that?

DAD-IO is going to be a multicenter, phase 2 trial looking at the combination of enfortumab vedotin at a full dose of 1.25 mg/kg with sacituzumab govitecan at 7.5 mg/kg on days 1 and 8 of each 21-day cycle with pembrolizumab [at 200 mg on day 1 of each cycle].

References

1. McGregor BA, Kwak L, Sonpavde GP, et al. Sacituzumab govitecan (SG) plus enfortumab vedotin (EV) for metastatic urothelial carcinoma (mUC) treatment-experienced (DAD) and with pembrolizumab (P) in treatment naïve UC (DAD-IO). J Clin Oncol. 2024;42(suppl 16):TPS4618. doi:10.1200/JCO.2024.42.16_suppl.TPS4618
2. McGregor BA, Sonpavde GP, Kwak L, et al. The Double Antibody Drug Conjugate (DAD) phase I trial: sacituzumab govitecan plus enfortumab vedotin for metastatic urothelial carcinoma. Ann Oncol. 2024;35(1):91-97. doi:10.1016/j.annonc.2023.09.3114