ADC Doublets Represent a Promising Novel Approach for Treatment-Resistant mUC

Bradley A. McGregor, MD

The non-overlapping toxicity profiles and synergistic payloads of the antibody-drug conjugates (ADC) sacituzumab govitecan-hziy (Trodelvy) and enfortumab vedotin-ejfv (Padcev) contribute to their safety and encouraging activity when administered in combination; this indicates the viability of ADC doublet therapy for the management of treatment-resistant metastatic urothelial cancer (mUC), according to Bradley A. McGregor, MD.

Initial findings from the phase 1 Double Antibody-Drug Conjugate (DAD) trial (NCT04724018) were presented at the 2023 ESMO Congress. At a median follow-up of 14.9 months, the regimen demonstrated 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), with 3 patients initially meeting PR criteria later achieving CR. Additionally, 3 patients achieved stable disease, 3 experienced disease progression, and 1 was not evaluable.

Response rates were high and occurred early across all 3 dose levels, and ongoing responses were observed in 9 patients. Additional analysis of anti-tumor activity revealed shrinkage in target lesions for 20 patients across all dose levels.

“This is a small phase 1 trial of 23 patients, but we showed that 2 ADCs can be given together safely. That has never been done before in any malignancy, to my knowledge, so this represents a novel approach,” said McGregor, who is a senior physician and the clinical director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, and an instructor of medicine at Harvard Medical School in Boston, Massachusetts.

In an interview with OncLive^®, McGregor expanded on the feasibility and safety considerations addressed through the design and methodology of the DAD study; highlighted dose-limiting toxicities (DLT) and early responses seen with the combination of sacituzumab govitecan plus enfortumab vedotin in treatment-resistant mUC; and explained how these results support further investigation of other ADC doublets as well as a planned evaluation of this ADC doublet alongside immunotherapy.

OncLive: What was the rationale for investigating sacituzumab govitecan in combination with enfortumab vedotin in the DAD trial?

McGregor: ADCs are a standard treatment in urothelial carcinoma. Sacituzumab govitecan and enfortumab vedotin are both approved by regulatory authorities for use in the treatment-resistant setting. Enfortumab vedotin's approval was based on phase 3 data and sacituzumab govitecan's approval was based on single-arm phase 2 data. These are different drugs with different targets, different payloads, and different toxicities. We combine chemotherapies together all the time, but to date there have been no studies combining ADCs in this malignancy. Given the different toxicity profiles, with some evidence of preclinical synergy for taxanes and irinotecan, we developed the phase 1 DAD trial to test the safety and tolerability of sacituzumab vedotin in combination with enfortumab vedotin through assessment of the maximum tolerated dose [MTD].

Please briefly describe the methodology and design of this study.

This was a phase 1 study, and we used a 3+3 [design]. There were 3 different dose levels. Dose level 1 was sacituzumab govitecan at 8 mg/kg with enfortumab vedotin at 1 mg/kg. Dose level 2 went up to 1.25 mg/kg [for enfortumab vedotin] with the same dose of sacituzumab govitecan. Dose 3 was a full dose of both [agents], [which was] 10 mg/kg of sacituzumab govitecan and 1.25 mg/kg of enfortumab vedotin. Treatment was given on day 1 and day 8 of a 21-day cycle until unacceptable toxicity or progression.

What feasibility and safety considerations guided dosing adjustments for these ADCs, and how were these assessed?

When we first designed the trial, there was concern that patients wouldn't go on to get the doublet for a long time and so patients had to get both drugs on day 1 of each cycle to continue. However, [administration of drugs on] day 8 could be held independently based on investigator assessment of toxicity. Patients were enrolled in a continuous fashion. Based on the DLT assessment, they either went up a dose level or down a dose level. DLTs were only assessed during cycle 1. As you think about what the results show, the MTD is based on the DLTs during cycle 1. Those DLTs include neutropenic fever, any non-hematologic toxicity that goes over 3 weeks, grade 3 non-hematologic toxicity over 3 weeks, any grade 3 neuropathy of any duration, any thrombocytopenic bleeding, or delay of therapy for over 3 weeks.

What should be known about the patient population enrolled onto the study?

We enrolled 23 patients, and the median age of patients was 70 years, with patients up to 88 years of age [included]. The majority of patients had [received] at least 2 prior lines of therapy, and only one patient progressed on immunotherapy alone. A quarter of them had a liver and/or bone mass, so these were not just lymph-node disease patients. Nine patients were enrolled on dose level 1, 8 enrolled on dose level 2, and 6 enrolled on dose level 3. Of the 6 patients on dose level 3, 1 patient who received the therapy during cycle 1 was unevaluable for DLT assessment.

Which dose level was selected for future studies based on the DLT outcomes?

What we saw overall is that the MTD was dose level 3, [consisting of the full dose of enfortumab vedotin and sacituzumab govitecan]. [However], there were 3 DLTs in the evaluable patients: one due to neutropenic fever, one due to delay in therapy for 3 weeks, and one due to mucositis. When we look at dose level 1, there were 2 DLTs and both were neutropenic fever. At dose level 2 there was 1 DLT, which was a delay in therapy for 3 weeks. That was due to enterocolitis. I will note that when the protocol first started, we did not allow the use of prophylactic granulocyte colony–stimulating factor [G-CSF] during cycle 1. [However], after we saw 2 out of the first 6 patients exhibit neutropenic fever and no other signs of toxicity, we allowed it by investigator's discretion, given that often investigators will give prophylactic G-CSF alongside sacituzumab govitecan. Subsequently, most patients on the trial got prophylactic G-CSF with cycle 1.

The caveat is that the MTD is the full dose with G-CSF support. We looked a bit further at this result. The recommended phase 2 dose is not the MTD. When we look at the patients on trial, the median number of cycles at the MTD was 1, so most patients quickly dose reduced. When we looked at dose level 2, [we saw] only one DLT and [that] most patients were able to [continue treatment for] at least 3 to 4 cycles. Given that enfortumab vedotin is approved at 1.25 mg/kg based on phase 3 data, dose level 2 was the recommended phase 2 dose.

Could you expand on the initial safety and efficacy findings reported at this year’s ESMO Congress?

The main point of the study was to look at safety and feasibility, and we showed [that combining these 2 ADCs] can be done. Obviously, there were some toxicities, [so we had to ask:] is it worth it? When we looked at the toxicity [profile] as a whole, no new toxicities [were seen with the combination]. Diarrhea, anemia, and neutropenia were the most common toxicities. There weren't any toxicities that stood out compared with these drugs as monotherapies. The rates of neuropathy weren't dramatically increased.

Then we start looking at efficacy, [which was a] key secondary end point. Twenty out of 23 patients had any degree of tumor shrinkage. This correlated with a confirmed ORR of 70%. We had 3 CRs on the trial, 3 patients with progressive disease as best response, and 9 patients whose responses are ongoing. Several of those patients are off therapy for a variety of reasons, with some having continued responses for over 18 months. The median follow-up right now is 14.9 months, which is early, but there are very encouraging signs [of activity thus far].

Are any further investigations of this ADC combination planned? What are the potential implications of this study for future treatment strategies in mUC?

We can potentially think about how to apply this [approach] to other cancers. Over a dozen ADCs are approved by the US [FDA]. Can we use other combinations of ADCs that are approved or in development together? That's a key point. What we did show is that [combining] enfortumab vedotin and sacituzumab govitecan can be done. Given together their MTD is full dose. The recommended 2 dose lowers the dose of sacituzumab govitecan just a bit, but that response is 70%.

[Based on these results, the combination] does merit further development. To that extent, we have a multicenter expansion cohort in development, looking at expanding the current DAD cohort. This [features] patients who are treatment resistant on platinum-based chemotherapy and immunotherapy. [Further studies are also] looking to combine [this ADC doublet] with immuno-oncology [IO agents] given the impressive results we're seeing for enfortumab vedotin and pembrolizumab [Keytruda] in the first line. This is also known as the DAD-IO [combination].

What other research in bladder cancer were you excited to see presented at the 2023 ESMO Congress?

This is an exciting conference for bladder cancer. For the first time ever, we have regimens that have improved upon the activity of cisplatin-based doublets in the frontline setting. The data for enfortumab vedotin and pembrolizumab vs platinum doublet chemotherapy will certainly be practice changing. As we see the data for cisplatin/gemcitabine plus nivolumab [Opdivo] and how that compares, it's going to be great to have more options for our patients in the future.

Editor’s Note: Dr McGregor reports consulting fees from Astellas Pharma, Bristol-Myers Squibb, Eisai, Exelixis, Gilead, Pfizer, and Seagen; he received institutional research funding from Aveo, Bristol-Myers Squibb, Exelixis, 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):S1199-S1200. doi:10.1016/j.annonc.2023.09.1009