Early-phase studies point to efficacy of a nectin-4-targeting antibody-drug conjugate in cervical cancer

Nectin-4 is emerging as an effective target owing to the very good objective response rates (ORRs) in pre-treated patients with recurrent/metastatic cervical cancer (J Clin Oncol. 2024;42(Suppl 16):3151; Gynecol Oncol. 2024;190(Suppl 1):S22–S23). Early-phase presentations at ESMO Gynaecological Cancers Congress 2026 (Copenhagen, 17–19 June) provide further evidence of the efficacy of bulumtatug fuvedotin (9MW2821), a next-generation nectin-4 antibody–drug conjugate (ADC) that has previously demonstrated encouraging antitumour activity and manageable tolerability in this setting (Ann Oncol. 2025;36:934–943).

In an update of a phase I/II study at a median follow-up of 21.3 months, a confirmed ORR of 32.1% and disease control rate (DCR) of 81.1% were reported in 53 evaluable patients with recurrent or metastatic cervical cancer (Abstract 28RO). Median overall survival (OS) was 19.4 months. Notably, similar benefit was achieved in the subgroup of 31 patients with prior exposure to immunotherapy: researchers reported an ORR of 29.0% and a DCR of 77.4%, while median OS was not reached.

“The ORRs are higher than we would usually anticipate for these patients,” notes Dr Camilla Nero from Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy, commenting on the data. The results with bulumtatug fuvedotin mirror those from a study of CRB-701, another next-generation nectin-4-targeted ADC, in patients with cervical cancer, which reported an ORR of 37.5% at the maximum 3.6 mg/kg dose (J Clin Oncol. 2026;44(Suppl 16):Abstract 5508). “There is also a non-negligible proportion of patients (49.1% and 58.2%, respectively) in the bulumtatug fuvedotin study who had progressed after bevacizumab and anti-PD-(L)1 therapies, which, alongside platinum-based chemotherapy, form the backbone of available therapies for these patients,” she continues. “This may suggest that a nectin-4-targeting ADC could provide a highly clinically relevant option for patients who progress after this treatment, where there is currently an unmet need.” A phase III confirmatory trial of bulumtatug fuvedotin versus physician’s choice of chemotherapy in patients with recurrent or metastatic cervical cancer is ongoing (NCT06692166).

Promising preliminary data were also discussed for bulumtatug fuvedotin in combination with the immune checkpoint inhibitor, toripalimab. In a review of preliminary efficacy and safety from 19 patients with metastatic cervical cancer enrolled in a single-arm phase Ib/II study, the majority of patients (84%) had not previously received systemic chemotherapy (Abstract 36P). In the efficacy-evaluable population (n=13), ORR was 76.9% (80% in the treatment-naïve group) and the DCR was 100%. The combination showed a manageable safety profile, with no new safety signals observed.

Although the ADC era in gynaecological cancers has begun, many questions remain over the optimal use of these agents, including gaining a better understanding of response in conditions of differing ADC target expression. “Current ADCs adopt targets that ignore the evolution of tumours and we do not tend to perform follow-up biopsies after treatment, which is essential for sequential treatment decisions,” Nero cautions. “There is also a need to precisely assess the ADC target expression in different metastatic sites, as well as design trials that take into account the fact that ADCs are chemotherapies and may not be appropriate candidates for maintenance strategies.”

According to a retrospective analysis presented in Copenhagen, correlating the expression of ADC targets with histotypes may also prove useful for profiling patients. Data showed that target expression varied according to histotype and there was a shift from diagnosis to recurrence across tumour specimens from 47 patients with cervical cancer and 93 patients with endometrial cancer (Abstract 73RO). CLDN6 and TROP2 were the most prevalent targets at diagnosis in both cancers, but alterations occurred over the disease course, with increases in CLDN6, B7H4, B7H3 and CDH6 expression at recurrence in endometrial cancer samples, and a marked increase in FOLR1-high expression at recurrence in cervical cancer specimens.

“Taken together, these studies underline the role that ADCs have to play in endometrial and cervical cancers and highlight that future research should aim to provide information on the predictive value of ADC target expression – with clearly defined and validated expression thresholds – to identify patients most likely to respond to treatment,” Nero concludes.