Journey Ends for Upifitamab Rilsodotin in NaPi2b+ Platinum-Resistant Ovarian Cancer

The NaPi2b-directed antibody-drug conjugate (ADC) upifitamab rilsodotin (UpRi; XMT-1536) showed modest activity in NaPi2b-positive patients with platinum-resistant high-grade serous ovarian cancer, with the overall response rate (ORR) failing to meet the criterion for the prespecified primary end point of the phase 1/2 UPLIFT trial (NCT03319628), according to Debra L. Richardson, MD, FACS, FACOG.

Results from the trial were presented during the 2024 SGO Annual Meeting on Women’s Cancer, and showed that upifitamab rilsodotin produced an ORR of 15.6% (95% CI, 10.0%-22.7%) in those with NaPi2b-positive disease (n = 141); it was 10.2% (95% CI, 5.6%-16.9%) in those with NaPi2b-low disease (n = 127). In the intention-to-treat population (n = 268), the ORR was 13.1% (95% CI, 9.3%-17.7%). These data suggest that the presence of NaPi2b does not enrich for response.

“The development of upifitamab rilsodotin was discontinued since it did not meet its primary objective in this trial,” said Richardson, who is an associate professor and chief of the Section of Gynecologic Oncology and Oklahoma TSET Phase I Program, at Stephenson Cancer Center of The University of Oklahoma (OU) College of Medicine, OU Health, in Oklahoma City.

In an interview with OncLive^®,Richardson discussed the rationale behind the development of upifitamab rilsodotin in platinum-resistant serous ovarian cancer, reported the agent’s efficacy and safety profile according to the UPLIFT trial, and highlighted other important research presented during the meeting.

OncLive: What was the rationale for conducting the UPLIFT trial?

Richardson: The rationale was to try and develop an ADC known as upifitamab rilsodotin in platinum-resistant serous ovarian cancer, and to show that it had sufficient efficacy. To continue development, we were hoping to [achieve] an ORR [with a] lower confidence interval [(CI) greater than] 12%, which is the expected response rate for standard-of-care chemotherapy.

Could you describe the mechanism of action for upifitamab rilsodotin? How does it compare with other ADCs in the space?

[Upifitamab rilsodotin] targets NaPi2b, which is a sodium-dependent phosphate transport protein that’s widely expressed in a lot of solid tumors, including high-grade serous ovarian cancer, fallopian tube, and primary peritoneal cancer. It was designed to have a controlled bystander effect, and to try and limit some of the toxicities that can be seen with certain ADCs including ocular toxicity, severe neutropenia, and neuropathy.

What key efficacy results were reported out from UPLIFT at this year’s SGO Annual Meeting?

This was a global, single-arm, phase 2 trial that enrolled [patients with] platinum-resistant recurrent ovarian cancer. Our primary outcome was ORR. In the NaPi2b-positive population, which was defined as having a tumor proportion score greater than or equal to 75%, that response rate was 15.6%. Unfortunately, we did not meet our primary outcome, and the lower CI [limit] did not exclude 12%. In the overall population, it was an ORR of 13%. It did not appear that our biomarker was enriched for response.

What toxicities were observed with upifitamab rilsodotin in this trial?

The adverse effect profile [primarily comprised] grade 1/2 toxicity. We did see some transient aspartate aminotransferase increase, some nausea, fatigue, anemia, and a decreased platelet count. In addition, there was some pneumonitis, which we expected; that [occurred in] about 9.6% [of patients]. We did see 5 grade 5 bleeding events, including 4 that were felt to be treatment related.

What other research were you most excited to see presented at the meeting?

I was excited to see Dr Moore’s presentation on raludotatug deruxtecan [DS-6000], which will be evaluated in patients with platinum-resistant ovarian cancer in the upcoming phase 2/3 REJOICE-Ovarian01 trial [NCT06161025]. I also was excited to see Dr Banerjee’s presentation on the [phase 2 RAMP 201 trial (NCT04625270)] of the RAF, MEK, and FAK inhibitor [avutometinib (VS-6766)] in low-grade serous ovarian cancer, as well as the overall survival update from [the phase 3 ENGOT-EN6-NSGO/GOG-3031/RUBY trial (NCT03981796)].

Reference

Richardson DL, Concin N, Hays JL, et al. UPLIFT (ENGOT-OV67/GOG-3048): Results from the phase II trial of upifitamab rilsodotin (UpRi; XMT-1536), a NaPi2b-directed dolaflexin antibody-drug conjugate in platinum-resistant ovarian cancer. Presented at the 2024 SGO Annual Meeting on Women’s Cancer; San Diego, CA; March 16-18, 2024.