Novel ADCs Show Responses in Ovarian and Cervical Cancer at ESMO 2026

Five abstracts presented at the 2026 European Society for Medical Oncology (ESMO) Congress in Madrid reported efficacy and safety data for antibody-drug conjugates (ADCs) in gynecologic cancers: 4 ADCs targeting folate receptor α (FRα) or B7-H4 in ovarian cancer and a subcutaneous HER2-directed ADC and PD-L1 inhibitor coformulation in cervical cancer.¹⁻⁵

ZW191 Produces Responses at 2 Doses in Heavily Pretreated PROC

In the first-in-human phase 1 study ZWI-ZW191-101 (NCT06555744), 80 patients with platinum-resistant ovarian cancer (PROC) who had progressed on available systemic therapies received ZW191, an FRα-targeted ADC, at 6.4 mg/kg (n = 37) or 9.6 mg/kg (n = 43) every 3 weeks.¹ Part 1 dose escalation enrolled 15 patients, and in part 2, 65 patients were randomly assigned 1:1 to the 2 doses regardless of histology, FRα expression, or number of prior lines. Median age was 61 years (range, 40-79), the median number of prior lines was 4 (range, 1-10), and prior therapy included platinum and taxane (100%), bevacizumab (Avastin; 84%), PARP inhibitors (56%), checkpoint inhibitors (19%), and mirvetuximab soravtansine-gynx (Elahere; 5%).

At a data cutoff of July 17, 2026, and a median follow-up of 5 months, the objective response rate (ORR) in response-evaluable patients with PROC other than clear cell carcinoma was 58% at both doses. The confirmed ORR was 52% at 6.4 mg/kg (n = 31), 45% at 9.6 mg/kg (n = 38), and 48% overall (n = 69), and the disease control rate was 100%, 92%, and 96%, respectively. Including patients with clear cell carcinoma (n = 78), the confirmed ORR was 44% overall. Median duration of response (DOR) was not reached, and 58% of patients (n = 23 per dose) remained on treatment.

Nausea occurred in 32% of patients at 6.4 mg/kg and 60% at 9.6 mg/kg, neutropenia in 19% and 42%, and anemia in 27% and 26%. Grade 3 or higher events included neutropenia (8% vs 23%), anemia (8% vs 14%), and pleural effusion (5% vs 9%). Updated DOR, progression-free survival (PFS), and efficacy by FRα expression will be presented.

Mocertatug Rezetecan Shows Dose-Dependent Activity in PROC

In the phase 1b dose-selection portion of BEHOLD-1 (NCT06431594), 136 patients with PROC were randomly assigned to mocertatug rezetecan (GSK5733584), a B7-H4–directed ADC composed of a humanized anti–B7-H4 IgG1 monoclonal antibody conjugated to a topoisomerase 1 inhibitor, at 2.8 mg/kg (n = 45), 4.8 mg/kg (n = 46), or 5.8 mg/kg (n = 45) every 3 weeks.² Patients had received a median of 2 prior lines of therapy (range, 1-5). The primary end point was investigator-assessed confirmed ORR per RECIST v1.1.

At a median follow-up of 13.4 months (data cutoff, June 30, 2026), the confirmed ORR was 36% (95% CI, 21.9%-51.2%) at 2.8 mg/kg, 57% (95% CI, 41.1%-71.1%) at 4.8 mg/kg, and 62% (95% CI, 46.5%-76.2%) at 5.8 mg/kg. Median DOR was 7.8, 6.9, and 12.2 months (95% CI, 7.0-12.7 at 5.8 mg/kg), and median PFS was 5.6, 8.3, and 11.1 months (95% CI, 8.3-13.9 at 5.8 mg/kg), respectively.

Among 135 patients who received at least 1 dose, grade 3 or higher treatment-related adverse events (TRAEs) occurred in 64 (47%) overall and in 32 (71%) of those who received 5.8 mg/kg. TRAEs led to discontinuation in 3% of patients overall and 2% at 5.8 mg/kg. Enrollment in the 5.8 mg/kg expansion cohorts is ongoing, and efficacy by B7-H4 expression cutoffs will be presented.

Torvutatug Samrotecan Shows Responses Across FRα Expression Levels

In the module 1 dose-optimization and expansion cohorts of the phase 1/2a FONTANA study (NCT05797168), 223 patients with PROC received torvutatug samrotecan (AZD5335), an FRα-targeted ADC with a topoisomerase 1 inhibitor payload, intravenously every 3 weeks.³ Of these patients, 71 were treated in dose escalation, 124 in dose optimization (FRα expression of at least 25% of tumor cells at 1+ or higher intensity), and 28 in additional expansion (FRα expression below 25%). Median duration of exposure was 7.1 months.

In the 143 patients treated at 1.6, 2.0, or 2.4 mg/kg in the expansion cohorts, the confirmed ORR was 56.6% (95% CI, 48.1-64.9; n = 81). By FRα expression, the confirmed ORR was 61.7% (95% CI, 48.2%-73.9%) in the high group (n = 60), 57.1% (95% CI, 44.0%-69.5%) in the low group (n = 63), and 40.0% (95% CI, 19.1%-63.9%) in the ultralow and null group (n = 20). Greater magnitude and duration of tumor reduction were observed at higher pharmacokinetic exposures, and circulating tumor DNA responses were seen across dose levels and FRα subgroups.

The most common treatment-emergent adverse events (TEAEs; any grade, grade 3 or 4) were nausea (76.7%, 5.4%), fatigue (59.2%, 6.3%), neutropenia (54.3%, 25.6%), vomiting (49.3%, 5.8%), and anemia (47.5%, 15.7%). TEAEs led to dose reduction in 26.5% of patients and discontinuation in 8.1%. The authors reported that the data informed the design of the phase 3 TREVI-OC-01 trial (NCT07218809), which is recruiting.

Sofetabart Mipitecan Plus Bevacizumab Is Active in Platinum-Sensitive Disease

In a phase 1 study (NCT06400472), 33 patients with platinum-sensitive ovarian cancer (PSOC) received sofetabart mipitecan (LY4170156), an FRα-targeted ADC with an Fc-silent humanized IgG1 antibody, a polysarcosine linker, and an exatecan payload, at 4 mg/kg plus bevacizumab at 15 mg/kg.⁴ The abstract noted that published data suggest patients with PSOC who have been exposed to PARP inhibitors have a reduced response to platinum-doublet chemotherapy. Median age was 67 years (range, 41-83), the median number of prior therapies was 3 (range, 1-6), and 70% and 67% of patients had received prior bevacizumab and PARP inhibitors, respectively.

At a median follow-up of 6 months (data cutoff, March 5, 2026), the ORR was 64% (95% CI, 45-80; 3 complete responses, 16 partial responses, and 2 unconfirmed partial responses), and the disease control rate was 100% (95% CI, 89%-100%). Of the 21 responders, 18 (86%) remained on treatment, and median DOR was not reached. The ORR was 59% (n = 13) in the 22 patients with prior PARP inhibitor exposure vs 73% (n = 8) in the 11 without, and 67% in patients with FRα expression of 75% to 100% (n = 12 of 18) and 0% to 74% (n = 8 of 12).

The most common TEAEs were nausea (73%), epistaxis (67%), fatigue (64%), anemia (58%), and neutropenia (55%); grade 3 or higher neutropenia occurred in 39.4%, including grade 3 febrile neutropenia in 3%. No keratopathy or high-grade peripheral neuropathy was reported, interstitial lung disease (ILD) occurred in 2 patients (6.1%; grade 2), and 1 patient (3%) discontinued treatment because of a TEAE. The data support the ongoing phase 3 FRAmework-01 study (NCT07213804), which is enrolling patients with PSOC in 2 parts based on prior PARP inhibitor exposure.

Subcutaneous JSKN033 Reaches 52.9% ORR in Pretreated Cervical Cancer

In the phase 1/2 JSKN033-102 trial (NCT06770881), 64 patients with pretreated advanced cervical cancer received JSKN033, a first-in-class subcutaneous fixed-dose coformulation of JSKN003, a biparatopic HER2-directed ADC, and envafolimab, a PD-L1 inhibitor.⁵ Patients were treated across 6 regimens at 6.7 mg/kg (n = 28) or 8.4 mg/kg (n = 36), including weekly, every-2-week, and loading schedules. Median age was 54 years, 31.3% had received 3 or more prior systemic lines, and 75%, 56.3%, and 10.9% had previously received immunotherapy, bevacizumab, and an ADC, respectively. Tumors were HER2 immunohistochemistry (IHC) 0 in 71.9% and HER2 IHC 1+ to 3+ in 15.6%, and 50% were PD-L1 negative (combined positive score [CPS] below 1) and 37.5% were PD-L1 positive (CPS of 1 or higher).

At a data cutoff of March 20, 2026, the ORR at 8.4 mg/kg was 52.9% (18 of 34 patients), the disease control rate was 88.2%, and median PFS was 7.2 months. The ORR at 6.7 mg/kg was 17.9% (5 of 28). Efficacy at 8.4 mg/kg was consistent across subgroups defined by HER2 expression, PD-L1 expression, and prior immunotherapy and bevacizumab treatment.

Grade 3 or higher TRAEs occurred in 26.6% of patients. The most common TRAE was injection site reactions (any grade, 95.3%; grade 3 or higher, 1.6%). No TRAE led to dose reduction, treatment discontinuation, or death, and ILD occurred in 1 patient. The investigators identified 8.4 mg/kg as the recommended phase 2 dose.

REFERENCES

1. Lee J-Y, Sommerhalder D, Perez Fidalgo JA, et al. Randomized dose optimization of ZW191 in heavily pretreated patients with platinum-resistant ovarian cancer (PROC). Presented at: 2026 ESMO Congress; October 23-27; Madrid, Spain. Abstract LBA40.

2. Salutari V, Lheureux S, Lim MC, et al. Mocertatug rezetecan (Mo-Rez) in patients with platinum-resistant ovarian cancer (PROC): updated results with longer follow-up from the global BEHOLD-1 study. Presented at: 2026 ESMO Congress; October 23-27; Madrid, Spain. Abstract LBA41.

3. Meric-Bernstam F, Shapira-Frommer R, Perets R, et al. Updated results from FONTANA: torvutatug samrotecan (torvu-sam), a folate receptor α (FRα)-targeted antibody-drug conjugate (ADC), in patients with platinum-resistant ovarian cancer (PROC). Presented at: 2026 ESMO Congress; October 23-27; Madrid, Spain. Abstract 1245RO.

4. Kyi C, Madariaga Urrutia A, Oaknin A, et al. Efficacy and safety of sofetabart mipitecan (Sofe-M), a folate receptor alpha (FRα) targeting antibody drug conjugate (ADC), plus bevacizumab (bev) in recurrent platinum (plat) sensitive ovarian cancer (PSOC). Presented at: 2026 ESMO Congress; October 23-27; Madrid, Spain. Abstract 1246RO.

5. Wu X, Tang D, Yang Z, et al. JSKN033, a first-in-class subcutaneous (SC)-injected fixed-dose combination (FDC) of biparatopic anti-HER2 ADC and PD-L1 inhibitor, in pre-treated cervical cancer. Presented at: 2026 ESMO Congress; October 23-27; Madrid, Spain. Abstract 1243RO.