Dr Richardson on the Safety of Upifitamab Rilsodotin in Platinum-Resistant 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 the safety profile of upifitamab rilsodotin (UpRi; XMT-1536) in the phase 1/2 UPLIFT trial (NCT03319628) of patients with ovarian cancer, and highlights other promising research presented during 

the 2024 SGO Annual Meeting on Women’s Cancer.

 offered insights into the efficacy and safety profile of upifitamab rilsodotin in platinum-resistant recurrent ovarian cancer. The agent produced an overall response rate (ORR) of 15.6% (95% CI, 10.0%-22.7%) in those with NaPi2b-positive disease (n = 141) fell short of meeting the predefined threshold for the trial’s primary end point, and the lower confidence interval limit did not exclude 12%. Based on these data, the development of upifitamab rilsodotin was discontinued since it did not meet its primary objective in this trial, she emphasizes.

Regarding safety, upifitamab rilsodotin displayed a manageable adverse effect (AE) profile, and was primarily associated with grade 1/2 toxicities, Richardson states. Elevations in aspartate aminotransferase, nausea, fatigue, anemia, and decreased platelet count were noted alongside an anticipated occurrence of pneumonitis in approximately 9.6% of patients, she elucidates. However, the emergence of grade 5 bleeding events, 4 of which were deemed treatment-related, underscores the importance of vigilant monitoring and management of potential complications associated with this therapy, Richardson reports.

In addition to the UPLIFT trial, noteworthy presentations at the 2024 SGO Annual Meeting included an overview of raludotatug deruxtecan (DS-6000) in platinum-resistant ovarian cancer, which is slated for evaluation in the upcoming phase 2/3 REJOICE-Ovarian01 trial (NCT06161025), Richardson continues. The phase 2 RAMP 201 trial (NCT04625270) exploring the RAF, MEK, and FAK inhibitor avutometinib (VS-6766) in low-grade serous ovarian cancer also piqued interest, along with a presentation of updated survival data from the phase 3 ENGOT-EN6-NSGO/GOG-3031/RUBY trial (NCT03981796), she says. These presentations collectively offer a comprehensive glimpse into the evolving treatment paradigm in ovarian cancer, highlighting novel therapeutic avenues and ongoing efforts to improve patient outcomes, Richardson concludes.

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Debra L. Richardson, MD, FACS, FACOG, discusses the safety profile of upifitamab rilsodotin in the phase 1/2 UPLIFT trial of patients with ovarian cancer.


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.

Debra L. Richardson, MD, FACS, FACOG, discusses outcomes seen with upifitamab rilsodotin in the phase 1/2 UPLIFT trial for patients with ovarian cancer. 

Dr Richardson on the Efficacy of Selinexor in TP53 Wild-Type Endometrial Cancer

Debra L. Richardson, MD, FACS, FACOG, associate professor and chief, Section of Gynecologic Oncology, Oklahoma TSET Phase I Program, Stephenson Cancer Center, The University of Oklahoma (OU) College of Medicine, OU Health, discusses the impact of selinexor’s (Xpovio) mechanism of action on the agent’s clinical efficacy in patients with 

 wild-type advanced or recurrent endometrial cancer.

The phase 3 ENGOT-EN5/GOG-3055/SIENDO trial (NCT03555422) evaluated maintenance therapy with selinexor in women with stage IV or primary relapsed endometrial cancer. Results from the primary analysis of the trial did not demonstrate improved median progression-free survival (PFS) with the investigational agent vs placebo for patients in the intention-to-treat population. However, a prespecified analysis of a subgroup of patients with 

 wild-type endometrial cancer demonstrated an encouraging PFS benefit, Richardson says.

presented at the 2023 IGCS Annual Global Meeting

, showing that selinexor (n = 77) produced a median PFS of 27.4 months (95% CI, 13.1-not reached [NR]) vs 5.2 months (95% CI, 2.0-13.1) with placebo (n = 36; HR, 0.41; 95% CI, 0.25-0.69; 1-sided nominal 

As an investigational oral XPO1 inhibitor, selinexor functions to block the XPO1-mediated export of many tumor suppressor proteins, Richardson explains. Its ability to promote the accumulation of tumor suppressor genes in the nucleus suggests a potential correlation with p53 functionality, she states. This mechanism may explain the agent’s notable efficacy in the 

Further stratification based on microsatellite stability status within the 

 wild-type population revealed improvements in PFS in patients with mismatch repair–proficient (pMMR) and deficient (dMMR) disease, with a more notable trend observed in the p53 wild-type pMMR population, Richardson reports. It’s important to approach these findings cautiously and recognize the need for validation through randomized trials, Richardson cautions.

The ongoing phase 3 XPORT-EC-042 trial (NCT05611931) aims to confirm these preliminary results and further shed light on potential associations between selinexor’s efficacy and specific molecular profiles, Richardson concludes.

Debra L. Richardson, MD, FACS, FACOG,  discusses the impact of selinexor’s mechanism of action on the agent’s clinical efficacy in patients with TP53 wild-type advanced or recurrent endometrial cancer.

Debra L. Richardson, MD, FACS, FACOG, associate professor, Section of Gynecologic Oncology, Oklahoma TSET Phase I Program, Stephenson Cancer Center, The University of Oklahoma (OU) College of Medicine, OU Health, discusses the rationale for the ongoing phase 3 UPNEXT trial in platinum-sensitive ovarian cancer.

Maintenance therapy options are being moved into the frontline setting for patients with ovarian cancer, which means that some patients who are eligible for maintenance treatment will have been previously treated with bevacizumab (Avastin) or a PARP inhibitor, either sequentially or in combination, Richardson says. However, no standard of care exists for these patients upon relapse, Richardson explains. Moreover, some patients are ineligible for current maintenance options because of comorbidities, Richardson adds.

As such, the UPNEXT trial is opening an opportunity to assess the antibody-drug conjugate upifitamab rilsodotin vs placebo as maintenance in patients with platinum-sensitive ovarian cancer. The trial will enroll patients with stable disease, as well as those with complete responses (CRs) or partial responses (PRs) to frontline therapy, Richardson continues. Currently, PARP inhibitors are not approved as maintenance therapy in this setting, so only patients with a prior CRs or PRs would be eligible for a PARP inhibitor, Richardson says. Overall, if a patient receives a PARP inhibitor in the up-front setting, it's unclear whether they could be rechallenges with another PARP inhibitor, Richardson concludes.

Debra L. Richardson, MD, FACS, FACOG, discusses the rationale for the ongoing phase 3 UPNEXT trial in platinum-sensitive ovarian cancer. 


Debra L. Richardson, MD, FACS, FACOG

Articles

Dr Richardson on the Safety of Upifitamab Rilsodotin in Platinum-Resistant Ovarian Cancer

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

Dr Richardson on the Efficacy of Selinexor in TP53 Wild-Type Endometrial Cancer

Dr. Richardson on the Rationale for the UPNEXT Trial in Ovarian Cancer