Dr Richardson on the UPLIFT Trial of Upifitamab Rilsodotin in Ovarian Cancer

Debra L. Richardson, MD, FACS, FACOG, associate professor, chief, Section of Gynecologic Oncology and Oklahoma, TSET Phase I Program, Stephenson Cancer Center, The University of Oklahoma (OU) College of Medicine, OU Health, discusses outcomes seen with upifitamab rilsodotin (UpRi; XMT-1536) in the phase 1/2 UPLIFT trial (NCT03319628) for patients with ovarian cancer. Notably, these data werepresented during the 2024 SGO Annual Meeting on Women’s Cancer.

Investigators aimed to demonstrate sufficient efficacy with the antibody-drug conjugate (ADC) upifitamab rilsodotin in platinum-resistant serous ovarian cancer, Richardson begins. The study aimed to achieve an objective response rate (ORR) exceeding 12% with the agent, which is a benchmark comparable to standard-of-care chemotherapy, she adds. The rationale behind this endeavor was to offer an alternative treatment option for patients with a limited therapeutic arsenal in this clinical setting, Richardson reports.

Upifitamab rilsodotin's mechanism of action involves the targeting of NaPi2b, a sodium-dependent phosphate transport protein prevalent in various solid tumors, including high-grade serous ovarian cancer, fallopian tube, and primary peritoneal cancer. This ADC was engineered to exhibit a controlled bystander effect while mitigating potential toxicities often associated with similar ADCs, such as ocular toxicity, severe neutropenia, and neuropathy, Richardson explains.

Despite the trial design and the agent’s targeted mechanism, results from the global, phase 2 UPLIFT trial demonstrated an ORR of 15.6% (95% CI, 10.0%-22.7%), in the NaPi2b-positive subgroup, defined as patients with a tumor proportion score of 75% or higher. This outcome fell short of the predetermined efficacy threshold, Richardson notes. Moreover, the overall ORR across the entire study cohort was 13.1% (95% CI, 9.3%-17.7%), she emphasizes. Contrary to expectations, there was no indication that the presence of NaPi2b significantly enriches for response, as observed in the biomarker-defined subgroup, Richardson adds.

The development of upifitamab rilsodotin was discontinued based on findings from UPLIFT, as it failed to meet its primary objective, Richardson explains. This outcome underscores the challenges in translating promising preclinical data into clinically meaningful outcomes, emphasizing the need for continued research and pursuit of effective treatments in platinum-resistant ovarian cancer, she concludes.