A phase 2 clinical trial investigating the antibody-drug conjugate (ADC) anetumab ravtansine has yielded disappointing results in the treatment of platinum-resistant/refractory high-grade serous ovarian cancer. The study, published in Clinical Cancer Research, was terminated early due to inferior efficacy compared to standard therapy.
Trial Results and Early Termination
The randomized study compared anetumab ravtansine plus bevacizumab against weekly paclitaxel plus bevacizumab. At the futility analysis, conducted after 35 progression-free survival (PFS) events, the anetumab ravtansine combination showed a median PFS of 5.3 months compared to 12.7 months in the paclitaxel arm (HR, 2.02; P = .03).
Response rates similarly favored the standard therapy arm, with an overall response rate of 66% for paclitaxel plus bevacizumab versus 21% for the anetumab ravtansine combination. The disease control rate was 86% and 71%, respectively.
Study Design and Patient Population
The trial enrolled patients with histologically confirmed high-grade serous or high-grade endometrioid ovarian, fallopian tube, or primary peritoneal cancer. Key eligibility criteria included:
- Platinum-resistant disease (platinum-free interval <6 months) or platinum-refractory disease
- Measurable disease per RECIST 1.1 criteria
- Positive mesothelin tumor expression (≥30% of tumor cells)
Patients were randomized 1:1 to receive either anetumab ravtansine (2.2 mg/kg weekly) or paclitaxel (80 mg/m2 weekly), both in combination with bevacizumab (10 mg/kg biweekly).
Safety Profile
The most common treatment-related adverse events in the anetumab ravtansine arm included:
- Elevated AST levels (86%)
- Elevated ALT levels (71%)
- Fatigue (64%)
- Thrombocytopenia (64%)
- Peripheral neuropathy (50%)
In the paclitaxel arm, frequent adverse events were:
- Anemia (79%)
- Neutropenia (69%)
- Fatigue (55%)
- Peripheral neuropathy (48%)
Biomarker Insights
The study yielded important biomarker findings, identifying several markers associated with worse PFS:
- Interleukin-6 (IL-6)
- VEGF
- PDGF-AA
- TGF-b1
Higher baseline IL-6 levels emerged as a potential negative prognostic marker for high-grade ovarian cancer, suggesting its possible role in predicting bevacizumab response.
Future Implications
Despite the negative outcome, researchers maintain that mesothelin remains a viable target for ADC development in high-grade ovarian cancer. The study also validated the clinical benefit of weekly paclitaxel/bevacizumab in this patient population, reinforcing its position as a standard treatment option.
The trial's early termination and limited sample size were noted as study limitations, along with the absence of somatic molecular profiling. These findings point to the need for continued research into novel therapeutic approaches for platinum-resistant ovarian cancer, while confirming the effectiveness of current standard treatments.
