  Dr Monk on the Investigation of B7-H4–Directed Vedotin ADCs in Gynecologic Cancers

Bradley Monk, MD, FACS, FACOG, professor, the Division of Gynecologic Oncology, University of Arizona College of Medicine and Creighton University School of Medicine; director, principal investigator, Community Research Development, HonorHealth Research Institute, vice president, member, the Board of Directors, the GOG-Foundation; co-director, GOG-Partners, discusses the rationale for investigating B7-H4–directed vedotin antibody-drug conjugates (ADCs) and highlights how these agents may address unmet needs for patients with gynecologic cancers.

The ongoing, phase 1 SGNB7H4V-001 trial (NCT05194072) is investigating the efficacy of the B7-H4–directed vedotin, SGN-B7H4V in patients with advanced solid tumors, Monk begins. Vedotin ADCs such as tisotumab vedotin-tftv (Tivdak) have previously demonstrated efficacy in patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy, Monk notes.

Preliminary findings from the trial, which were presented at the 

, highlighted the promising activity of SGN-B7H4V in diverse cancer types, Monk states. The trial evaluated different dosing schedules, comparing administration on days 1 and 8 of a 21-day cycle with administration of the agent on days 1 and 15 of 28-day cycles, he details. Initial data suggest robust activity and support the safety profile observed with both dosing schedules, he says.

Among 28 patients with breast cancer, 7 achieved objective responses, while 4 out of 20 patients with ovarian cancer responded to the treatment. Notably, a complete response was observed in 1 of 16 patients with endometrial cancer, and the drug had activity in lung and biliary tract cancers. The responses were characterized as early, deep, and durable.

Adverse effects associated with SGN-B7H4V were comparable to that of other vedotin ADCs, Monk continues. Fatigue, neuropathy, and bone marrow suppression were all common, while diarrhea levels remained low. Notably, alopecia and pneumonitis were rare occurrences, Monk notes.

These results contribute valuable toward the development of targeted therapies for various solid tumors, exemplified by the early and durable responses seen with SGN-B7H4V, Monk says. The findings also support ongoing efforts to advance the understanding of ADCs and their potential in treating patients with advanced solid tumors, he adds. Furthermore, the study's exploration of dosing schedules offers information for optimizing the administration of SGN-B7H4V, Monk emphasizes. The every-other-week schedule emerged as a preferred choice based on its demonstrated efficacy and safety. Further research may pave the way for the continued development and potential clinical application of SGN-B7H4V in the treatment landscape of advanced solid tumors, Monk concludes.

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Bradley Monk, MD, FACS, FACOG, discusses the rationale for investigating B7-H4–directed vedotin antibody-drug conjugates and highlights how these agents may address unmet needs for patients with gynecologic cancers.

Dr Monk on the Investigation of B7-H4–Directed Vedotin ADCs in Gynecologic Cancers

Bradley Monk, MD, FACS, FACOG, professor, the Division of Gynecologic Oncology the University of Arizona College of Medicine and Creighton University School of Medicine; director, principal investigator, Community Research Development, HonorHealth Research Institute, vice president, member, the Board of Directors, the GOG-Foundation; co-director, GOG-Partners, discusses findings from the phase 2 RAMP 201 trial (NCT04625270) in patients with low-grade serous ovarian cancer and the importance of these results within the context of the larger ovarian cancer treatment paradigm. 

Mature findings from RAMP 201, which were presented at the 2023 ASCO Annual Meeting, included data with 31 evaluable patients with low-grade serous ovarian cancer who received the RAF/MEK inhibitor avutometinib (VS-6766) and 29 evaluable patients with low-grade serous disease who received avutometinib plus the FAK inhibitor defactinib (VS-6063). The patients who received the combination achieved an overall response rate (ORR) of 45%, including ORRs of 60% in those with 

 wild-type disease. In the monotherapy arm, the ORR was 10%, including ORRs of 13% in those with 

 wild-type disease. In addition, the tumor shrinkage rate was 86% with the combination vs 90% with the monotherapy.

In RAMP 201, the median time to response was 5.5 months in the combination arm compared with 7.3 months in the monotherapy arm. The tolerability of avutometinib plus defactinib allowed 83% ± 20% of patients in part A of the trial to maintain the combination dose intensity, Monk says. In the monotherapy arm, 80% ± 20% of patients in part A maintained dose intensity.

The ORR achieved with avutometinib plus defactinib in this population exceeds those seen with other MEK inhibitors in patients with ovarian cancer, Monk explains. Previously, in 2022, the phase 2/3 GOG 281/LOGS trial (NCT02101788) evaluated the efficacy of the MEK inhibitor trametinib (Mekinist) vs standard-of-care (SOC) chemotherapy in patients with recurrent low-grade serous ovarian cancer and found that trametinib elicited an ORR of 26% vs 6% with SOC. Additionally, in 2020, findings from the phase 3 MILO trial (NCT01849874), which investigated the efficacy of the MEK inhibitor binimetinib (Mektovi) vs chemotherapy in patients with recurrent or persistent low-grade ovarian, fallopian tube, or primary peritoneal serous carcinoma, demonstrated an ORR of 16% with binimetinib vs 13% with chemotherapy.

Furthermore, in the phase 1 FRAME trial (NCT03875820), avutometinib plus defactinib produced an ORR of 46% in the 24 evaluable patients treated with the combination. These findings supported the 2021 FDA breakthrough therapy designation for the combination in this population. In the RAMP 201 and FRAME trials combined 53 patients received avutometinib plus defactinib, of whom 45% and 46%, respectively, had clinically meaningful responses with the combination, Monk concludes.

Bradley Monk, MD, FACS, FACOG, discusses findings from the phase 2 RAMP 201 trial in patients with low-grade serous ovarian cancer and the importance of these results within the context of the larger ovarian cancer treatment paradigm. 

Bradley Monk, MD, FACS, FACOG

Articles

Dr Monk on the Investigation of B7-H4–Directed Vedotin ADCs in Gynecologic Cancers

Dr Monk on Avutometinib Plus Defactinib in Low-Grade Serous Ovarian Cancer