Upifitamab Rilsodotin Under Investigation in Several Trials to Bridge Unmet Need in Recurrent Ovarian Cancer

Debra L. Richardson, MD, FACS, FACOG

The NaPi2b-directed antibody-drug conjugate (ADC) upifitamab rilsodotin (UpRi; XMT-1536) is being evaluated in several ongoing clinical trials to assess the agent’s utility as maintenance therapy in patients with platinum-resistant or platinum-sensitive recurrent ovarian cancer, said Debra L. Richardson, MD, FACS, FACOG, who added that UpRi has the potential to fulfill an unmet need in ovarian cancer that has been left by standard maintenance options moving into earlier lines of treatment.

“We are seeing maintenance therapy moving up to the frontline [setting for patients with] ovarian cancer, so many patients will be retreated with bevacizumab [Avastin] and/or PARP inhibitor maintenance, either sequentially or in combination,” Richardson said.

“There is no standard of care upon relapse for those patients and some patients are ineligible for those current maintenance options because of comorbidities. UpRi offers another potential [maintenance] option as an ADC for patients with recurrent ovarian cancer,” Richardson added.

In an interview with OncLive^®, Richardson, an associate professor in the Section of Gynecologic Oncology of the Oklahoma TSET Phase I Program at Stephenson Cancer Center of The University of Oklahoma (OU) College of Medicine of OU Health, discusses the role of NaPi2b as a target for UpRi, data that have emerged from the ongoing phase 1/2 UPLIFT trial (NCT03319628), and the development of other studies like UPNEXT and UPGRADE (NCT04907968) that are further evaluating UpRi in patients with ovarian cancer.

OncLive^®: What is the mechanism of action of UpRi and the rationale to target NaPi2b in ovarian cancer?

Richardson: NaPi2b is a sodium-dependent phosphate transport protein. It is a lineage marker and is not an oncogene. It is widely expressed in ovarian cancer with limited expression in normal tissues. Some other ADCs under development in ovarian cancer target other antigens, like mirvetuximab soravtansine that targets folate receptor [alpha] and other ADCs targeting mesothelin. UpRi is a first-in-class dolaflexin ADC, which has a controlled bystander effect.

How does the drug-to-antibody ratio of UpRi compare with that of other ADCs?

It’s pretty high at about 10, so it is a little higher [compared with a typical ADC].

What are your thoughts on the early efficacy and safety data from the UPLIFT trial with UpRi?

They look promising. The overall response rate [ORR] for the 75 evaluable patients we have so far was 23%. In the patients who are NaPi2b high, [the ORR] was 34%. The duration of response was about 5 months [in the NaPi2b-high patients].

The most common adverse effects [AEs] we are seeing are fatigue, nausea, vomiting, pyrexia, and some transient aspartate transaminase elevations. We have not seen severe neutropenia, ocular toxicity, or peripheral neuropathy that can be seen with other ADCs.

What patient population is being enrolled in the UPLIFT trial and what are the key study objectives?

[The UPLIFT trial] is targeting platinum-resistant patients with 1 to 4 prior lines of therapy, so somewhat heavily pretreated patients. If patients only have had 1 to 2 prior regimens, prior bevacizumab is required. Patients can be enrolled with grade 2 peripheral neuropathy. The primary objective is ORR.

How is NaPi2b being assessed to determine which patients have high expression?

[NaPi2b] is retrospectively assessed. Tissue is obtained [through] archival or fresh biopsy if archival tissue is not available. A tumor proportion score is calculated; if it is greater than or equal to 75%, the patient is considered NaPi2b high. This represents about two-thirds of the population.

How have the data suggested that giving UpRi at lower doses can improve toxicity?

When given at 36 mg/m² compared with 43 mg/m², we saw less grade 3/4 fatigue and grade 3 or greater pneumonitis. No patients treated to date at the 36 mg/m² dose have had grade 3 or higher pneumonitis. Lower dosing led to fewer treatment-related dose reductions, but there was a similar ORR [to the higher dose]. Lower dosing also led to longer treatment duration and less discontinuations before the first scan.

What are the next steps for the UPLIFT trial? How would positive results affect the treatment of patients with ovarian cancer?

We just started enrolling in April 2021. We are planning [to enroll] about 180 patients. We are hoping that this trial will be positive. If it is, the goal would be to have another agent available for patients with platinum-resistant ovarian cancer. This is a registration trial.

How is the patient population being evaluated in the UPNEXT trial different from that of the UPLIFT trial?

UPNEXT is enrolling platinum-sensitive patients vs platinum-resistant patients and they do have to be NaPi2b high, which is not a requirement to go on UPLIFT. Patients can have had 1 to 3 prior platinum regimens. Those are the key differences between UPLIFT and UPNEXT.

In the UPNEXT trial, we are going to have patients with stable disease who are eligible in addition to [patients with] complete responses [CRs] and partial responses [PRs]. PARP inhibitors are not included as maintenance in this setting, so only patients who had CRs or PRs would be eligible for PARP inhibitors in that setting. If patients had PARP inhibitors up front, it is unclear who we can rechallenge with PARP inhibitors at this point.

Patients can have had prior bevacizumab and PARP inhibitors. If patients are BRCA mutated, it is required that they had prior PARP inhibitor therapy to be enrolled on the trial.

What is the design of UPNEXT and what are the main goals of the study?

[UPNEXT] is a randomized phase 3 trial. After induction with platinum-based therapy, patients will be randomized to UpRi or placebo as maintenance. The primary outcome is progression-free survival.

How could positive results from UPNEXT change practice patterns for patients with platinum-sensitive recurrent ovarian cancer?

We hope the study is going to be positive, but it is a confirmatory trial for UPLIFT. Assuming UPLIFT is positive and UpRi does get accelerated approval from the FDA, [the UPNEXT] trial would hopefully lead to full approval of UpRi from the FDA. If positive, it would give this maintenance option to patients with platinum-sensitive recurrent ovarian cancer.

The UPGRADE trial, which is also in development, is looking at UpRi in combination with other agents. What are the goals of this research?

[UPGRADE] is a phase 1 dose-escalation trial followed by a dose-expansion portion of carboplatin with UpRi in patients with platinum-sensitive recurrent ovarian cancer. NaPi2b expression will not be required to enter the trial, but it will be retrospectively assessed on tissue. Carboplatin will be given for up to 6 cycles as is traditionally done; however, this trial will continue UpRi until either [limiting] toxicity or progression.

If the trial is successful, this would allow us to have another platinum doublet for the treatment of patients with platinum-sensitive recurrent ovarian cancer.

Are there any other studies you are keeping an eye on to further expand upon the utility of ADCs in ovarian cancer?

This is an exciting time for patients with recurrent ovarian cancer with the topline results of SORAYA [NCT04296890] coming out in the fall [of 2022]. Hopefully we will see an accelerated approval for mirvetuximab soravtansine. That confirmatory trial is ongoing.