GSK B7-H4 ADC Shows 62 Percent Response But Without Randomized Proof

GSK's Mo-Rez Shows Durable Responses in Platinum-Resistant Ovarian Cancer

GSK announced updated positive data from the global phase Ib BEHOLD-1 trial for mocertatug rezetecan (Mo-Rez), an investigational B7-H4-targeted antibody-drug conjugate, in platinum-resistant ovarian cancer (PROC). The results, presented at ESMO 2026, showed a confirmed objective response rate (cORR) of 62% and a median duration of response (DoR) of 12.2 months at the selected phase III dose of 5.8 mg/kg, with a median progression-free survival (PFS) of 11.1 months. These clinically meaningful and durable responses, observed at over 13 months follow-up, support the acceleration of a large-scale phase III development program across gynaecological cancers, including five pivotal studies now underway. The safety profile remained manageable and consistent with previous data.

• The BEHOLD-1 trial demonstrated robust efficacy in platinum-resistant ovarian cancer, achieving a confirmed objective response rate (cORR) of 62% (n=28/45) with a 95% confidence interval of 46.5-76.2%. Patients experienced a median duration of response (DoR) of 12.2 months (95% CI: 7.0-12.7) and a median progression-free survival (PFS) of 11.1 months (95% CI: 8.3-13.9) at the selected phase III dose of 5.8 mg/kg, indicating durable disease control in a difficult-to-treat setting.
• Mocertatug rezetecan exhibited a manageable safety profile consistent with previously published data. Grade ≥3 treatment-related adverse events (TRAEs) were observed in 71% (n=32/45) of patients, predominantly haematologic. Importantly, TRAEs led to treatment discontinuation in only 2% (n=1/45) of patients, and interstitial lung disease (ILD)/pneumonitis occurred in 2% (n=1/45) of patients, suggesting a favorable tolerability for the drug.
• Building on these promising phase Ib results, GSK has significantly accelerated the development of Mo-Rez, with five pivotal phase III studies now underway across various gynaecological cancers. This broad program includes platinum-resistant, platinum-sensitive, and first-line maintenance settings for ovarian cancer, as well as second-line advanced/recurrent and first-line maintenance settings for endometrial cancer, underscoring the drug's potential across a range of B7-H4 expression levels.

The Persistent Challenges in Platinum-Resistant Ovarian Cancer

Platinum-resistant ovarian cancer follows relapse after platinum-based therapy and is associated with poor survival and poor prognosis. Standard of care treatment options have limited efficacy from traditional cytotoxic agents and are generally palliative in nature and rarely have realistic potential to be curative.

• Complex and evolving resistance biology: Resistance can be intrinsic or acquired, with intracellular mechanisms including restoration of homologous recombination repair, reduced intracellular accumulation of platinum, blocked cellular replication and inhibition of apoptosis, acting in concert with immunosuppressive, angiogenic and stromal changes in the tumour microenvironment, with capacity to evolve over time.

• Lack of predictive stratification: Current molecular stratification lacks prognostic and predictive validity, limited in part by the extreme genomic complexity of high-grade serous ovarian cancer, with low response rates to immune checkpoint inhibition in unselected advanced ovarian cancer populations and no validated biomarkers predictive of response.

• Limited activity of standard cytotoxics: Single-agent weekly AUC2-carboplatin appeared to be inactive by response criteria in a homogenously defined population, and single-agent generic gemcitabine showed modest efficacy with overall response rate of 12.1% and median progression free survival of 2 months and overall survival of 10 months.

• Toxicity-constrained delivery: Prolonged aggressive chemotherapy makes therapy-related toxicities a major factor in treatment decisions, with hematologic toxicity as the main reason for dose modification, palmoplantar erythrodysesthesia and stomatitis as main reasons for discontinuation, and higher incidences of hypertension, mucositis, proteinuria, diarrhea, and hand-foot syndrome with combination therapy.

• Trial and evidence gaps: No randomized head-to-head trials comparing nab-paclitaxel and sb-paclitaxel in platinum-resistant ovarian cancer exist, with existing nab-paclitaxel studies limited to single-arm and combination trials with heterogeneous populations, and a need for correlative studies to elucidate predictive biomarkers and endpoints that can appropriately measure benefit for palliative treatments.

Mo-Rez's Promising Efficacy and Safety Profile from BEHOLD-1

Recent studies in platinum-resistant ovarian cancer have evaluated folate receptor alpha-targeting antibody-drug conjugates, bevacizumab-containing regimens, and novel gene-based combinations. Mirvetuximab soravtansine has demonstrated improved response and survival outcomes in FRα-positive disease, while other approaches have shown variable efficacy.

• MIRASOL trial (NCT04209855) – mirvetuximab soravtansine-gynx (MIRV) 6 mg per kilogram of adjusted ideal body weight every 3 weeks versus investigator's choice of chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan): median progression-free survival was 5.62 months (95% confidence interval [CI], 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001), objective response occurred in 42.3% versus 15.9% (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001), and overall survival was median 16.46 months vs. 12.75 months (hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P=0.005); fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%).

• SORAYA trial (NCT04296890) – single-arm phase II mirvetuximab soravtansine-gynx 6 mg/kg adjusted ideal body weight intravenously once every 3 weeks in FRα-high patients with 1 to 3 prior therapies including required bevacizumab: objective response rate was 32.4% (95% CI, 23.6 to 42.2), including five complete and 29 partial responses, median duration of response was 6.9 months (95% CI, 5.6 to 9.7), and final median overall survival was 15.0 months (95% CI, 11.5 to 18.7); most common treatment-related adverse events (all grade and grade 3-4) were blurred vision (41% and 6%), keratopathy (29% and 9%), and nausea (29% and 0%), with dose delays, reductions, and discontinuations in 33%, 20%, and 9% of patients, respectively.

• OVAL Study/GOG 3018 (NCT03398655) – ofranergene obadenovec (ofra-vec, VB-111) intravenously every 8 weeks with once a week IV paclitaxel versus placebo with paclitaxel: median progression-free survival was 5.29 months in the ofra-vec arm and 5.36 months in the control arm, hazard ratio (HR) 1.03 (CI, 0.83 to 1.29; P = .7823), median overall survival was 13.37 months versus 13.14 months, HR 0.97 (CI, 0.75 to 1.27; P = .8440), and objective response rates were 28.9% with ofra-vec versus 29.6% with control; safety profile was characterized by common transient flu-like symptoms such as fever and chills.

• AURELIA trial (NCT00976911) – investigator-selected single-agent chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, or topotecan) alone or with bevacizumab (10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks): progression-free survival hazard ratio was 0.48 (95% CI, 0.38 to 0.60), median progression-free survival was 3.4 months with chemotherapy alone versus 6.7 months with bevacizumab-containing therapy, RECIST objective response rate was 11.8% versus 27.3% (P = .001), and overall survival hazard ratio was 0.85 (95% CI, 0.66 to 1.08; P < .174; median OS, 13.3 v 16.6 months, respectively); Grade ≥ 2 hypertension and proteinuria were more common with bevacizumab, and GI perforation occurred in 2.2% of bevacizumab-treated patients.

Expanding Mo-Rez's Potential Across Gynaecological Cancers

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Mo-Rez: High Efficacy Poised to Reshape Gynecologic Cancer Treatment

The recent update on mocertatug rezetecan (Mo-Rez) in platinum-resistant ovarian cancer (PROC) marks a potentially pivotal moment for patients facing this challenging diagnosis. With a confirmed objective response rate of 62% and a median duration of response exceeding a year, these Phase Ib results suggest a significant leap forward in efficacy compared to existing options. For context, previous efforts to enhance standard chemotherapy with agents like sorafenib in ovarian cancer have shown no improvement in efficacy and increased toxicity, underscoring the difficulty of achieving meaningful clinical benefit in this disease. Similarly, other investigational therapies in recurrent ovarian cancer have demonstrated lower response rates, highlighting Mo-Rez's standout performance.

The strategic decision to accelerate Mo-Rez into five pivotal Phase III studies across various gynecological cancers reflects strong confidence in its B7-H4-targeted antibody-drug conjugate mechanism. This broad development plan could establish Mo-Rez as a foundational therapy, potentially reshaping treatment paradigms beyond PROC. However, this ambitious expansion also brings critical considerations. Ensuring robust and diverse patient enrollment in these large-scale trials is paramount, especially given documented historical under-representation of minority women in gynecologic cancer immunotherapy trials. Such disparities could affect the generalizability of results and equitable access to this promising therapy.

Furthermore, while the safety profile has been manageable to date, the long-term tolerability and full spectrum of adverse events in a larger, more diverse patient population will be crucial for widespread adoption. The oncology landscape is constantly evolving, and Mo-Rez will need to maintain its competitive edge against emerging therapies or novel combination strategies. Nevertheless, these data offer a compelling vision for improved patient outcomes in gynecological cancers, positioning the B7-H4 target as a validated pathway for future therapeutic innovation.