Dual ADC Combination Shows Promising Efficacy with 71% ORR in Heavily Pretreated Metastatic Urothelial Cancer

Oct 19, 2023 17:45 CST Updated 17:45

Gilead Sciences

Antiviral Drug Developer

▎Traceability

In the development of ADCs, a common phenomenon is the simultaneous expression of multiple targets in the same tumor, with no significant differences. When developing different targets with the same toxin, tumors are likely to develop resistance to that toxin, leading to reduced efficacy of subsequent treatments using the same toxin and creating potential competition. The development of ADCs with different toxins and different targets may become the preferred strategy moving forward. Combining different antibodies carrying different payloads can, to a certain extent, maximize therapeutic efficacy due to the differing mechanisms of the toxins and their distinct targets.

For example, Nectin4 MMAE ADC and TROP2 SN38 ADC have both been approved for the indication of urothelial carcinoma. There is a certain basis for their combination use.

Recently, Gilead Sciences announced at ESMOPreliminary Data from the Phase I Combination Clinical Trial of Dual ADCs: Sacituzumab Govitecan (SG) and Enfortumab Vedotin (EV) as a Second-Line Treatment for Metastatic Urothelial Carcinoma (mUC).

Patients enrolled had an ECOG score of ≤1, had previously received platinum-based chemotherapy and immunotherapy but experienced disease progression, or were unsuitable for cisplatin and had already undergone first-line treatment. The medication regimen consisted of SG+EV administered in 21-day cycles, with dosing on Day 1 and Day 8 of each cycle, until the occurrence of unacceptable toxicity or disease progression. To evaluate the feasibility and safety of the combination of SG+EV, the dose was adjusted based on the incidence of dose-limiting toxicities (DLTs) during Cycle 1 (C1) and the total number of patients treated across four predetermined dose levels (DL), using a Bayesian Optimal Interval design (details provided in the table). Adverse events (AEs) were assessed using CTCAE 5.0.

From May 2021 to April 2023, this clinical trial enrolled 24 patients (9 in DL1, 9 in DL2, and 6 in DL3). As of May 1, 2023, 23 patients were available for DLT evaluation, with one patient in DL3 never starting treatment. The median age was 69 years (range: 41-88), and 22 patients had received at least two prior lines of therapy. In DL1, two patients experienced febrile neutropenia (FN), after which prophylactic granulocyte colony-stimulating factor (GCSF) was used; a total of 18 patients received GCSF. Across all dose levels, 70% of patients experienced grade ≥3 adverse events, including one grade 5 adverse event (PossiblePneumonia associated with EV occurred in C2 (a patient of DL3).The table below summarizes the DLT status at corresponding dose levels, with DL2 selected for future studies. Among 21 patients evaluable for efficacy, the objective response rate was 71% (15/21), including 2 complete responses and 13 partial responses; 2 patients experienced disease progression.With a median follow-up time of 11.9 months, responses were ongoing in 11/15 patients for durations ranging from 1.1+ months to 21.6+ months.

SG+EV Demonstrates High Safety in Treating Patients with Refractory Urothelial Carcinoma, with an Objective Response Rate of 71%. Further Expansion of the Dual-ADC Cohort Is Ongoing, While Triple Therapy Combining with Immunotherapy Is Also Being Explored.

Regarding the development of dual-toxin monoclonal antibody ADCs, there have always been some voices within the industry. However, this form of ADC is more challenging to develop, with much higher requirements for conjugation methods, and it is also difficult to control the toxicity in the later stages. Nowadays, Gilead's development strategy has instead become a good choice. The combination of toxins with different targets and mechanisms can, to a certain extent, maximize efficacy. There are increasingly more approaches in the ADC field, and subsequently, more combination strategies are emerging. Currently, the concept of combining ADC with PD-1 inhibitors has been validated.

The exploration of innovative drugs is becoming increasingly interesting. It will not be abandoned due to a decrease in capital enthusiasm.

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