Sacituzumab Govitecan Plus Enfortumab Vedotin Shows Early Promise in Metastatic Urothelial Carcinoma

Bradley A. McGregor, MD

Combining the antibody-drug conjugates (ADCs) sacituzumab govitecan-hziy (Trodelvy) and enfortumab vedotin-ejfv (Padcev) was safe, feasible, and produced high and early response rates in patients with treatment-resistant metastatic urothelial cancer, according to findings from the phase 1 Double Antibody Drug Conjugate (DAD) trial (NCT04724018) presented during the 2023 ESMO Congress.

At a median follow-up of 14.9 months, the doublet elicited an overall response rate (ORR) of 70% (95% CI, 47%-87%) across all dose levels (n = 23); this included 3 complete responses (CRs) and 13 partial responses (PRs). Notably, 3 patients who initially met the criteria for a PR later achieved a CR. Three patients achieved stable disease, another 3 patients experienced disease progression, and 1 patient was not evaluable.

When broken down by dose level, ORRs were 78% (95% CI, 40%-97%) for dose level 1 (n = 9), 75% (95% CI, 35%-97%) for dose level 2 (n = 8), and 50% (95% CI, 12%-88%) for dose level 3 (n = 6). Responses are ongoing in 9 patients. The 12-month progression-free survival (PFS) and overall survival (OS) rates were 41% (95% CI, 18%-62%) and 86% (95% CI, 61%-95%), respectively.

Moreover, 20 patients experienced any degree of shrinkage in target lesions across all dose levels. However, 1 patient with a reduction in the target lesion went on to experience progressive disease due to the emergence of a non-target lesion.

“DAD is the first trial to show that ADCs can be given safely in combination—not just in urothelial carcinoma, but in any malignancy,” lead study author Bradley A. McGregor, MD, of Dana-Farber Cancer Institute, said during a presentation of the data. “...Not only are patients having prolonged responses [with the combination] ...but a lot of patients [who stopped] treatment for a variety of reasons show ongoing responses.”

Sacituzumab govitecan and enfortumab vedotin are currently used sequentially in the management of treatment-resistant metastatic urothelial carcinoma. Despite belonging to the same drug class, these drugs have key differences in their targets, payloads, and toxicity profiles, McGregor noted.

“If we look at the major toxicities we’re concerned about, there’s not much overlap,” he said. “...So, it is rational to think that maybe these drugs can be safely given together. There’s also preclinical data [showing] that the payloads have some synergistic activity.”

Based on their toxicity profiles and the potential synergy of their payloads, investigators sought to assess the safety and maximum tolerated dose (MTD) of sacituzumab govitecan combined with enfortumab vedotin in this population.

The study enrolled patients with metastatic urothelial carcinoma who had an ECOG performance status of 0 or 1 and had experienced disease progression on platinum-based therapy and immunotherapy or progression on 1 line of treatment and were ineligible for cisplatin. Patients were required to have acceptable organ function.

If they had small cell carcinoma, active central nervous system metastases, ongoing toxicities that were grade 2 or higher from prior therapy, previous exposure to either of the ADCs, or uncontrolled diabetes mellitus, they were excluded.

The study utilized a Bayesian Optimal Internal Design to determine the number of patients treated at each predefined dose level and to establish the MTD of the combination during cycle 1.

Treatment involved the administration of sacituzumab govitecan and enfortumab vedotin on days 1 and 8 of a 21-day treatment cycle until disease progression or unacceptable toxicities. Patients were administered 1 of 3 dose levels. Dose level 1 consisted of 8 mg/kg of sacituzumab govitecan plus 1 mg/kg of enfortumab vedotin. Dose level 2 increased the dosage of enfortumab vedotin to 1.25 mg/kg with the same dose of sacituzumab govitecan as dose level 1. Dose 3 included a full 10 mg/kg dose of sacituzumab govitecan plus 1.25 mg/kg of enfortumab vedotin.

Notably, either therapy could be held on day 8 independently based on investigator assessment of toxicity. Patients then underwent a dose-limiting toxicity (DLT) assessment, after which they either escalated, retained, or de-escalated the dose level. DLTs were only assessed during cycle 1.

The primary objective of the study was to assess the frequency of DLTs during the first treatment cycle. Secondary end points included evaluating ORR, PFS, and OS.

DLTs included neutropenic fever, any non–grade 3 hematologic toxicity with a duration of more than 1 week or requiring a 3-week interruption of therapy, any grade 3 neuropathy of any duration, and thrombocytopenic bleeding.

A total of 24 patients were enrolled onto the study between May 2021 and April 2023.

One patient did not initiate therapy and was thus excluded from the DLT assessment. Of the 23 patients who underwent treatment, 9 patients were enrolled on dose level 1, 8 enrolled on dose level 2, and 6 enrolled onto dose level 3. The data cutoff date for the analysis was August 28, 2023, and the median follow-up was 16.4 months (range, 0.1-37.4).

The median age of patients was 70 years (range, 41-88), and 78% were male. Racial demographics revealed that 83% of patients were White, 9% were Asian, and 9% were Hispanic or Latino. The majority of patients had an ECOG performance status of 0 (61%), and pure urothelial histology (70%). The primary disease site for most patients was the bladder (70%), followed by the upper tract (26%) and the urethra (4%). Metastatic sites included the lymph nodes (74%), bone (26%), liver (26%), lung (22%), and kidney (13%). Almost all patients had received prior immunotherapy (96%) and platinum-based chemotherapy (96%). Regarding the number of prior lines of therapy, 48% of patients received 2 prior lines, 48% had received 3 to 5 lines, and 4% had received 1 line.

Despite the occurrence of 3 DLTs, the MTD was identified as dose level 3. DLTs observed at this dose level included febrile neutropenia, mucositis, and a delay in treatment for 3 weeks. Notably, the initial study protocol was modified to allow the use of prophylactic granulocyte colony–stimulating factor (GCSF) during cycle 1 at the investigator’s discretion. This was enacted after the first 6 patients had already enrolled.Subsequently, 5, 7, and 6 of the patients treated at dose level 1, 2, and 3, respectively, received GCSF support. Of these, 3, 6, and 6 were treated with prophylactic GCSF during cycle 1.

A cumulative assessment of toxicities and median number of cycles identified dose level 2 as the recommended phase 2 dose. At dose level 3, the median number of cycles for both ADCs in the combination was 1 (range 1-14). Accordingly, 3 patients underwent a single dose reduction for sacituzumab govitecan and enfortumab vedotin each, 1 patient underwent 2 dose reduction for sacituzumab govitecan, and 3 underwent 2 dose reductions for enfortumab vedotin. Conversely, the median number of cycles for both ADCs at dose level 2 was 7 (range, 1-15). Two patients were treated with a one reduced dose of sacituzumab govitecan, and 1 patient received 2 dose reductions of enfortumab vedotin. For dose level 1, the median number of cycles was 9 for sacituzumab govitecan (range, 2-19) and 4 for enfortumab vedotin (range, 1-19). Four patients experienced a single dose reduction for the former ADC, and 1 for the latter. An additional 2 patients experienced 2 dose reductions for sacituzumab govitecan and enfortumab vedotin, respectively.

Regarding safety, no new toxicities were seen with the combination. The most common any-grade toxicities regardless of dose level were diarrhea (grade 1, 52.2%; grade 2, 26.1%; grade 3, 8.7%), anemia, (17.4%; 21.7%; 34.8%), and neutropenia (13.0%; 21.7%; 17.4%). Other frequent adverse effects (AEs) included fatigue (34.8%; 21.7%; 8.7%), alopecia (13.0%; 47.8%; 0.0%), peripheral sensory neuropathy (21.7%; 34.8%; 0.0%), nausea (30.4%; 8.7%; 4.3%), alanine aminotransferase increase (34.8%; 8.7%; 0.0%), aspartate aminotransferase increase (39.1%; 4.3%; 0.0%), weight loss (13.0%; 17.4%; 0.0%), alkaline phosphatase increase (26.1%; 4.3%; 0.0%), rash (26.1%; 4.3%; 0.0%), dry eye (17.4%; 8.7%; 0.0%), constipation (21.7%; 4.3%; 0.0%), dysgeusia (21.7%; 4.3%; 0.0%), watering eyes (21.7%; 4.3%; 0.0%), hypomagnesemia (17.4%; 4.3%; 0.0%), pruritis (4.3%; 17.4%; 0.0%), hypophosphatemia (4.3%; 13.0%; 0.0%), urinary tract infection (0.0; 4.3%; 13.0%) and anorexia (8.7%; 4.3%; 4.3%). The only grade 4 AE was neutrophil count decrease (17.4%).

Based on these findings, studies evaluating sacituzumab govitecan and enfortumab vedotin alone or in combination with pembrolizumab (Keytruda; DAD-IO) are currently in development.

“The DAD [combination is] not coming to your clinic tomorrow, but I think that [this trial] is very exciting, and it supports the premise that we should be exploring [ADC doublets] further,” McGregor concluded.

Disclosures: Dr McGregor received consulting fees from Astellas, Bristol Myers Squibb, Eisai, Exelixis, Gilead, Pfizer, and SeaGen. Research funding to institution was received from Aveo, Bristol Myers Squibb, Exelixis, Gilead, Pfizer, and SeaGen.

Reference

McGregor BA, Sonpavde GP, Kwak L, et al. 2360O The double antibody drug conjugate (DAD) phase I trial: Sacituzumab govitecan (SG) plus enfortumab vedotin (EV) as ≥ second-line therapy for metastatic urothelial carcinoma (mUC). Ann Oncol. 2023;34(suppl 2):S0923-S7534. doi:10.1016/j.annonc.2023.09.3114