Dana M. Chase, MD, and Angeles Alvarez Secord, MD, MHSc, discuss mocertatug rezetecan in gynecologic malignancies.
After displaying a robust overall response rate (ORR) with a manageable safety profile as monotherapy in the phase 1 BEHOLD-1 study (NCT06431594), the novel B7-H4–directed antibody-drug conjugate (ADC) mocertatug rezetecan (Mo-Rez) is set to be evaluated as a combination component in the phase 1/2 BEHOLD-2 study (NCT06796907), according to Dana M. Chase, MD, and Angeles Alvarez Secord, MD, MHSc.
“[Some] of the novel targets [for ADCs] includes the immune checkpoint molecules B7-H3 and B7-H4; those two molecules are known to be overexpressed in both ovarian and endometrial cancers, and that makes them an ideal target,” Chase said in an interview with OncLive® alongside Secord. “They also have potent potential immunosuppressive roles in the microenvironment. Those two characteristics make these ideal targets and unique in their immune regulatory characteristics.”
Chase is a professor of clinical obstetrics and gynecology in the Division of Gynecologic Oncology at UCLA Health in Los Angeles, California.
Secord is a professor of obstetrics and gynecology and a member of the Duke Cancer Institute in Durham, North Carolina.
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Among patients with PROC who received Mo-Rez at 5.8 mg/kg (n = 34), the confirmed ORR was 62% (95% CI, 44%-78%). Additionally, at a median follow-up of 6.1 months (interquartile range [IQR], 3.7-6.8), the median time to response (TTR) was 1.4 months (IQR, 1.4-1.6) in these patients. Patients with PROC who received Mo-Rez at 2.8 mg/kg (n = 35) and 4.8 mg/kg (n = 34), achieved respective confirmed ORRs of 31% (95% CI, 17%-49%) and 53% (95% CI, 35%-70%). At respective median follow-ups of 6.1 months (IQR, 5.1-6.5) and 6.0 months (IQR, 2.9-7.0), the median TTR values were 2.7 months (IQR, 1.4-2.8) and 2.6 months (IQR, 1.5-2.8), respectively.
Patients with recurrent or advanced EC cohort who received Mo-Rez at 4.8 mg/kg (n = 12) experienced a confirmed ORR of 67% (95% CI, 35%-90%) and a median TTR of 1.5 months (IQR, 1.2-2.7) at a median follow-up of 4.2 months (IQR, 1.7-5.8). At a median follow-up of 4.0 months (IQR, 1.4-5.8), the confirmed ORR was 9% (95% CI, 0.2%-41%) and the median TTR was 1.4 months (IQR, 1.4-1.4) in the 2.8-mg/kg group (n = 11).
“It was really outstanding to see an ORR of over 60% in patients with PROC,” Secord said. “We may be getting a little spoiled by seeing these high response rates across the board with ADCs, but with traditional chemotherapy the ORRs are actually remarkably low, probably 15% or less. [Above] 60% was amazing and it absolutely supports further evaluation within a phase 3 setting.”
In terms of safety, patients in the PROC cohort experienced any-grade treatment-related adverse effects (TRAEs) at rates of 93%, 86%, and 95% in the 2.8-mg/kg, 4.8-mg/kg, and 5.8-mg/kg groups, respectively. Grade 3 or higher TRAEs occurred in 19%, 42%, and 64% at these 3 respective doses. Moreover, TRAEs leading to dose interruption or delay were reported in 5%, 28%, and 39% of these patients, and TRAEs leading to dose reduction occurred in 0%, 14%, and 39%, respectively. TRAEs leading to treatment discontinuation were reported in 0%, 5%, and 0% of patients at these respective dose levels. Treatment-related serious adverse effects (SAEs) occurred in 5%, 12%, and 18% of patients. One treatment-related fatal SAE was reported at the 5.8 mg/kg dose.
In the recurrent or advanced EC cohort, any-grade TRAEs were reported in 92% of patients at both the 2.8-mg/kg and 4.8-mg/kg dose levels. Grade 3 or higher TRAEs occurred in 17% of patients at 2.8 mg/kg and 54% at 4.8 mg/kg. TRAEs leading to dose interruption/delay were reported in 13% and 21% of patients, respectively; TRAEs leading to dose reduction occurred in 0% and 17% of patients. TRAEs leading to treatment discontinuation were reported in 4% of patients at both dose levels. Treatment-related SAEs occurred in 0% and 8%, and 1 fatal SAE was reported in the 4.8 mg/kg EC cohort, though it was not considered treatment-related.
“The BEHOLD-1 data told us told us that, overall, the toxicities from Mo-Rez are pretty tolerable,” Chase noted. “There were some cytopenias, nausea, or GI toxicity, but very few grade 3 or 4 events that would make us concerned for things such as ocular toxicity or interstitial lung disease. It really doesn't look like there's much overlapping toxicity with Mo-Rez on top of a checkpoint inhibitor.”
BEHOLD-2 is examining the safety, tolerability, pharmacokinetics, and clinical activity of Mo-Rez in combination with other anti-cancer agents in participants with advanced solid tumors.2 Part 1A of the study will evaluate Mo-Rez in combination with dostarlimab (Jemperli) in patients with EC with confirmed mismatch repair proficient or microsatellites stable tumor status per local test. Patients in part 1A must have also experienced disease progression on or be intolerant to at least 1 prior line of standard systemic therapy and not be candidates for curative external radiotherapy or brachytherapy.
Part 2A will examine Mo-Rez with or without bevacizumab (Avastin) in patients with advanced ovarian cancer, fallopian tube, or peritoneal cancer that has relapsed over 6 months from the last dose of platinum prior to enrollment. Patients must also have experienced disease progression on or be intolerant to at least 1 prior line of standard systemic therapy and not be candidates for a second cytoreductive surgery.
The primary end points in part A are the rate of dose-limiting toxicities and other safety measures; in part B the primary end point is confirmed ORR. Secondary end points include duration of response, progression-free survival, overall survival, and pharmacokinetic measures.
“Once [ADCs like Mo-Rez] are available, I will probably utilize a biomarker-[selected] type approach to figure out how to proceed,” Secord said. “Additionally, it's going to be convenience of dosing [discussion]; an every 2-week strategy vs something that's every 3-weeks or longer strategy is going to be more appealing in terms of patients' convenience, and then the AE profile. Patients' prior toxicity from therapy will probably be part of that decision-making process as well.”
