Upifitamab Rilsodotin Misses Primary End Point in Ovarian Cancer

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The antibody-drug conjugate (ADC) upifitamab rilsodotin (UpRi; XMT-1536) did not meet its primary end point of investigator-assessed objective response rate (ORR) in patients with ovarian cancer, according to a press release from Mersana Therapeutics.¹

According to topline results from the phase 1b/2 UPLIFT trial (NCT03319628), 22 out of 141 NaPi2b-positive patients responded for an investigator-assessed ORR of 15.6% (95% CI, 10.0%-22.7%) when receiving UpRi, which targets NaPi2b. The median duration of response (ORR) in this population was 7.4 months.

“We are deeply disappointed that UPLIFT’s efficacy failed to replicate previous data from approximately 100 patients in the dose expansion portion of our phase 1b clinical trial,” Arvin Yang, MD, PhD, senior vice president and chief medical officer of Mersana Therapeutics, said in the press release. “While the duration of response was longer than that from the dose expansion portion of UpRi’s phase 1b clinical trial, the lower bound of the confidence interval for the primary end point did not meet our goal of excluding a 12% ORR seen with standard-of-care single-agent chemotherapy.”

UpRi is a first-in-class ADC targeting the sodium-dependent phosphate transport protein NaPi2b. In previous reporting of the dose expansion phase 1b portion of the trial, 34% (13/38) of NaPi2b-positive patients responded including 2 complete responses (CRs).² The DOR was 5 months in this subgroup. In the overall evaluable population of the dose expansion cohort, the confirmed ORR was 23% and the disease control rate was 72%.

As of the data cutoff on May 31, 2023, the UPLIFT trial enrolled 268 patients, 141 of whom were NaPi2b-positive, which was defined as having a tumor proportion score of at least 75%.¹ Patients had platinum-resistant ovarian cancer and had received a median of 3 prior lines of therapy, with 31% having received 4 prior lines. These included bevacizumab (Avastin) in 84% and PARP inhibitor in 69%. Patients received 36 mg/m² UpRi up to a maximum dose of approximately 80 mg every 4 weeks.² The primary end point was investigator-assessed ORR in the NaPi2b-positive patients, with secondary end points including investigator-assessed ORR in all patients, ORR by independent radiological review (IRR), DOR, and safety.¹

In the NaPi2b-positive patients, there were 20 partial responses (PRs; 14.2%) and 2 CRs (1.4%) by investigator assessment. The IRR assessment reported 16 PRs (11.3%) and 7 CRs (5.0%) for an ORR of 16.3% (95% CI, 10.6%-23.5%). The DOR was not reached according to the IRR.

In the total population of 268 patients, the investigator-assessed ORR was 13.1%, including 32 PRs (11.9%) and 3 CRs (1.1%); the DOR was 7.4 months. The IRR-assessed ORR was 13.1% including 24 PRs (9.0%) and 11 CRs (4.1%) with a DOR of 10.7 months.

According to Mersana’s announcement, the safety and tolerability data were consistent with prior reporting. In the dose expansion portion, the most frequent adverse events (AEs) were fatigue, nausea, transient AST (aspartate aminotransferase) increase, thrombocytopenia, and decreased appetite.² The most common grade 3 or higher AES were transient AST increase, fatigue, anemia, and thrombocytopenia. Dose reductions were required in 28% and discontinuations in 10% in the dose expansion portion.

UpRi is also being investigated in combination with carboplatin in patients with high-grade serous ovarian cancer in the phase 1 UPGRADE trial (NCT04907968) and as maintenance in patients with platinum-sensitive recurrent ovarian cancer compared with placebo in the phase 3 randomized UP-NEXT trial (NCT05329545).

“We are in the process of conducting an in-depth analysis of various factors to better understand the results as well as the characteristics of patients who responded to UpRi therapy, particularly those whose responses were deep and durable,” said Yang.¹ “We extend our deepest gratitude to all of the patients, family members, caregivers and investigators who contributed to UPLIFT.”

_References:

_{1. Mersana Therapeutics announces topline data from UPLIFT clinical trial in patients with platinum-resistant ovarian cancer and strategic reprioritization. News release. Mersana Therapeutics. July 27, 2023. Accessed August 1, 2023. https://tinyurl.com/2p9y83f9}

_{2. Richardson D, Hamilton E, Barve M, et al. Updated results from the phase 1 expansion study of upifitamab rilsodotin (UpRi; XMT-1536), a NaPi2b-directed dolaflexin antibody drug conjugate (ADC) in ovarian cancer (076). Gyn Oncol. 2021;166(suppl 1):S48. doi:10.1016/S0090-8258(22)01294-X}