Raludotatug Deruxtecan Elicits Early Efficacy and Safety in Platinum-Resistant Ovarian Cancer

The emerging CDH6-directed antibody-drug conjugate (ADC) raludotatug deruxtecan (R-DXd; DS-6000) had a manageable safety profile, generated pharmacokinetic activity, and produced early evidence of clinical response in patients with heavily pretreated, platinum-resistant ovarian cancer, according to initial findings from a subgroup analysis of a phase 1 study (NCT04707248).¹

Preliminary efficacy data presented during the 2023 ESMO Congress showed that efficacy-evaluable patients treated with R-DXd at doses ranging from 4.8 mg/kg to 8.0 mg/kg (n = 50) of the dose-escalation and -expansion study experienced a confirmed overall response rate (ORR) of 46% (95% CI, 32%-61%). This ORR consisted of 1 complete response and 22 partial responses. Notably, 4 unconfirmed responses were ongoing at the time of data cutoff.

Additional efficacy assessment revealed that the disease control rate with R-DXd in this cohort was 98%, and the median time to response was 6 weeks (95% CI, 5-11). At a median follow-up of 5.8 months (range, 1.4-16.8), the median duration of response was 11.2 months (95% CI, 3.0-not evaluable). The median progression-free survival was 7.9 months (95% CI, 4.4-12.4) at a median follow-up of 5.6 months (range, 0.03-25.1).

“R-DXd is the first ADC targeting CDH6 [that has been] tested in ovarian cancer, and demonstrates very strong signals of efficacy,” Kathleen N. Moore, MD, MS, lead study author and the associate director of Clinical Research at Oklahoma University Health Stephenson Cancer Center in Oklahoma City, stated in an oral presentation of the data.

Although the treatment armamentarium in folate receptor alpha (FRα)–positive platinum-resistant ovarian cancer has recently expanded with the FDA’s accelerated approval of mirvetuximab soravtansine-gynx (Elahere),² novel, innovative therapies are still necessary to address the challenges associated with treating patients with this disease subtype.

“The treatment for tumors considered platinum resistant remains a high unmet need [in ovarian cancer]. Until recently, we'd gone a decade without a new approval in this space. While the FDA approval of mirvetuximab soravtansine is certainly welcome, it only applies to the 35% of tumors that are FRα-high, so we've turned to other tumor-associated antigens," Moore explained.¹

Investigators have noted that overexpression of the cell adhesion protein CDH6 occurs in approximately 65% to 85% of patients with ovarian cancer and is associated with poor prognosis. The CDH6-directed ADC R-DXd may therefore be a promising treatment option to explore for patients with this mutation, Moore said. The agent consists of a humanized anti-CDH6 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload through a tetrapeptide-based cleavable linker.

Accordingly, investigators designed a first-in-human phase 1 study to evaluate the safety and preliminary efficacy of R-DXd for patients with advanced or metastatic platinum-resistant ovarian cancer who were not able to receive standard-of-care therapy.Patients were required to have an ECOG performance score (PS) of 0 or 1, been previously treated with a taxane or platinum-based chemotherapy, and be naive to CDH6-targeting agents or ADCs with a linked topoisomerase I inhibitor.

“[Notably,] pre-testing for CDH6 positivity was not required for participation in this study, but was looked at in a prospective fashion,” Moore added.

The two-part study consisted of a dose-escalation phase (part A) and dose-expansion phase (part B). In part A, patients were intravenously (IV) administered 1 of 6 escalating doses of R-DXd once every 3 weeks: 1.6 mg/kg, 3.2 mg/kg, 4.8 mg/kg, 6.4 mg/kg, 8.0 mg/kg, or 9.6 mg/kg. Patients with ovarian cancer in the dose-expansion cohort received 1 of 4 doses of IV R-DXd once every 3 weeks: 4.8 mg/kg, 5.6 mg/kg, 6.4 mg/kg, or 8.0 mg/kg. The current analysis included patients who received doses of R-DXd between 4.8 mg/kg and 8.0 mg/kg in both parts.

The study’s primary end points were safety and tolerability; ORR per RECIST v1.1 criteria in the dose-expansion cohort; and the determination of both the maximum tolerated dose and recommended doses for expansion. Key secondary end points included the pharmacokinetics of the ADC, the total anti-CDH6 antibody, and the DXd payload; antitumor activity per RECIST v1.1 criteria; and immunogenicity.

At the data cutoff of July 14, 2023, 60 patients were enrolled in the study to receive the agent at doses ranging from 4.8 mg/kg to 8.0 mg/kg. Of these patients, 13, 8, 24, and 15 were treated with the 4.8 mg/kg, 5.6 mg/kg, 6.4 mg/kg, or 8.0 mg/kg doses, respectively. A total of 33 patients were still on study treatment at the time of data cutoff, including 9, 8, 13, and 3 patients at each respective dose level. Twenty-seven patients discontinued treatment because of disease progression (n = 14), clinical progression (n = 2), treatment-emergent adverse effects (TEAEs; n = 9), or other reasons (n = 2). The median duration of treatment was 18 weeks (range, 3-115), with 12 patients being treated for 6 months or longer and 3 patients continuing treatment for 18 months or more.

The median age of patients of these 60 patients was 66 years (range, 42-82), and the median baseline tumor CDH6 expression H-score was 125 (range, 0-250). Most patients had an ECOG PS of 1 (63.3%), and 91.7% had platinum-resistant disease. Patients had received a median of 4 prior systemic regimens (range, 1-13), including bevacizumab (Avastin; 68.3%) or a PARP inhibitor (65.0%).

The efficacy-evaluable population included patients who received at least 1 dose of R-DXd and completed at least 1 post-baseline tumor assessment or discontinued treatment for any reason. Changes from baseline in target tumor size were assessed according to RECIST v1.1 criteria. Importantly, 2 patients with no measurable lesions at baseline and 1 patient who discontinued treatment and did not have a post-baseline tumor assessment were excluded from the efficacy analysis.

The safety analysis (n = 60) revealed that the agent was associated with a manageable toxicity profile consistent with that associated with other DXd ADCs. Any-grade TEAEs were observed in 95.0% of patients in this population, 51.7% of which were grade 3 or higher. TEAEs were associated with treatment discontinuation, dose interruptions, or dose reductions in 15.0%, 36.7%, and 25.0% of patients, respectively. Treatment-related AEs (TRAEs) of grade 3 or higher were seen in 36.7% of patients, and 3.3% of these were associated with death.

The most frequently observed TRAEs, which occurred in 10% or more of the population, were nausea (any-grade, 58.3%; grade ≥3, 1.7%), fatigue (45.0%; 3.3%), vomiting (33.3%; 1.7%), anemia (28.3%; 18.3%), decreased neutrophil counts (25.0%; 11.7%), diarrhea (26.7%; 1.7%), decreased appetite (25.0%; 1.7%), decreased platelet count (16.7%; 5.0%), alopecia (11.7%; 0.0%), and malaise (10%; 0.0%).

“The AEs seen in the study were predominantly common, but low-grade, gastrointestinal effects that happened in cycle 1 during the dose-limiting toxicity period when we [did not use prophylactics] for nausea and vomiting,” Moore clarified when discussing the safety data. “Once we were able to [use prophylactics] in subsequent cycles, these AEs were mitigated. The rest of the AEs are what you’d expect with this class of agents.”

Regarding the incidence of interstitial lung disease (ILD), 3.3% of patients (n = 2) experienced grade 5 ILD, both of whom were in the 8.0 mg/kg cohort; both incidents were deemed treatment related. Moreover, 8.9% (n = 4) of patients in the 4.8 mg/kg to 6.4 mg/kg cohorts experienced grade 2 ILD, including 2 cases of which were adjudicated as treatment related.

Notably, the 8.0 mg/kg cohort was closed in October 2022 because of a higher incidence of serious and grade 3 or higher TEAEs, the overall pharmacokinetic activity of R-DXd, and an unfavorable risk/benefit profile.

“This reinforces the practice of early recognition, early initiation of steroids, and dose holds when ILD events are suspected,” Moore stated.

Dose assessment will continue at the remaining 3 dose levels, and a late-phase study further evaluating R-DXd in patients with ovarian cancer is imminent.

Editor’s note: Dr Moore reported receiving a research grant from Verastem; serving as an advisor for Novartis, OncXerna, Onconova, Panavance, VBL Therapeutics, Verastem, Zentalis, Regeneron, Exelixis, Gilead, GOG Partners; serving as an invited Speaker for Research To Practice, OncLive®, PRIME Therapeutics, PER, Great Debates and Updates; serving as principal investigator for OncXerna; serving on the board of directors for ASCO and GOG Foundation; and receiving funding from Daiichi Sankyo.

References

1. Moore K, Philipovskiy A, Harano K, et al. Raludotatug deruxtecan (R-DXd; DS-6000) monotherapy in patients with previously treated ovarian cancer (OVC): subgroup analysis of a first-in-human phase I study. Ann Oncol. 2023;34(suppl 2):S510. doi:10.1016/j.annonc.2023.09.1924
2. FDA grants accelerated approval to mirvetuximab soravtansine-gynx for FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or peritoneal cancer. News release. FDA. November 14, 2022. Accessed November 16, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-mirvetuximab-soravtansine-gynx-fra-positive-platinum-resistant