Raludotatug deruxtecan (R-DXd) is a potential groundbreaking investigational CDH6-directed ADC, representing a first-of-its-kind. Formulated using Daiichi Sankyo's exclusive DXd ADC technology, raludotatug deruxtecan consists of a humanized anti-CDH6 IgG1 monoclonal antibody linked to several topoisomerase I inhibitor payloads (specifically, an exatecan derivative, DXd) through cleavable linkers based on tetrapeptides. The ongoing Phase I trial is the inaugural human assessment, focusing on examining the safety and efficacy of raludotatug deruxtecan in patients with advanced ovarian cancer resistant or refractory to standard care and previously treated with platinum-based and taxane chemotherapy.

Recent findings from a subgroup analysis unveiled at ESMO 2023, based on a Phase I trial, indicate that raludotatug deruxtecan (R-DXd) maintains its encouraging clinical efficacy in individuals with extensively treated advanced ovarian cancer resistant to platinum-based therapies.

In the Phase I trial, patients with measurable ovarian cancer receiving raludotatug deruxtecan (4.8 to 8.0 mg/kg) exhibited a confirmed objective response rate (ORR) of 46% as assessed by investigators. This included one complete response (CR), 22 partial responses (PRs), and four unconfirmed responses. The observed disease control rate (DCR) reached 98%. As of the data cutoff on July 14, 2023, the median duration of response (DOR) stood at 11.2 months, and the median progression-free survival (PFS) was 7.9 months. These responses were evident across patients with varying levels of tumor CDH6 expression.

The safety profile of raludotatug deruxtecan remained consistent with previous reports from the Phase I trial. Treatment discontinuations due to treatment-emergent adverse events (TEAEs) were observed in 15% of patients. Grade 3 or higher TEAEs occurred in 51.7% of patients. The most prevalent Grade >3 or higher TEAEs included anemia (18.3%), decreased neutrophil count (11.7%), decreased platelet count (5.0%), fatigue (3.3%), nausea (1.7%), vomiting (1.7%), diarrhea (1.7%), and decreased appetite (1.7%). Across the doses of 4.8 to 6.4 mg/kg, two confirmed Grade 2 interstitial lung disease (ILD) events were identified as treatment-related. Furthermore, two Grade 5 treatment-related ILD events were reported at the 8 mg/kg dose, leading to its discontinuation as of October 2022.

The majority of patients (91.7%) presented with platinum-resistant disease, having undergone a median of four prior lines of systemic therapy, including bevacizumab (68.3%) and a PARP inhibitor (65%). The median follow-up for duration of response (DOR) was 5.8 months, while the median follow-up for progression-free survival (PFS) was 5.6 months. The median treatment duration reached 18 weeks, and currently, 33 patients are still undergoing treatment with raludotatug deruxtecan.

KOL insights

“Following treatment with the current standard of care of platinum-based chemotherapy, disease progression in patients with advanced ovarian cancer is inevitable and underscores the need for new treatment options. The response rate seen in these heavily pretreated patients is promising and further study of raludotatug deruxtecan in ovarian cancer is warranted.”– MD, United States.

Conclusion

Daiichi Sankyo kicked off the European Society for Medical Oncology (ESMO) Congress with a game-changing moment: a substantial USD 4 billion upfront deal granting Merck rights to their next three promising antibody-drug conjugate (ADC) candidates. In addition to the upfront payment, Daiichi stands to receive USD 1.5 billion in continuation payments over the next 24 months and up to USD 16.5 billion in sales milestones. These are exceptional figures for licensing deals, particularly in the current landscape. Daiichi's strategy is clear-cut: expedite the entry of the three ADCs into clinical trials. The frontrunner is patritumab deruxtecan (HER3-DXd), a HER3-directed ADC currently undergoing pivotal trials in EGFR-mutated non-small cell lung cancer. The other two candidates, ifinatamab deruxtecan (I-DXd), a B7-H3-directed ADC, and raludotatug deruxtecan (R-DXd), targeting CDH6 overexpressed in kidney, ovarian, and other cancers, are in Phase II and Phase I stages, respectively. Considering that an estimated 65% to 85% of patients with ovarian cancer have expression of CDH6, we expect that the company is eyeing on a specific and untapped market in ovarian cancer.

For more insight into Ovarian Cancer, their respective geographical patient burden, treatment, and changing market landscape-related advancements, refer to these reports:

• Advanced Recurrent Ovarian Cancer Market Insight and Market Forecast
• Ovarian Cancer Market Insight and Market Forecast
• Clear Cell Ovarian Cancer Market Insight and Market Forecast
• Low Grade Serous Ovarian Carcinoma Market Insight and Market Forecast
• Platinum-Resistant Relapsed Ovarian Cancer Market Insight and Market Forecast