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)

Objectives: Effective and well-tolerated treatments for platinum-resistant ovarian cancer (PROC) remain a substantial unmet medical need; single-agent chemotherapy, which is the standard of care, has limited efficacy (response rate ≤12%). Upifitamab Rilsodotin (UpRi) is a first-in-class Dolaflexin ADC targeting NaPi2b, a sodium-dependent phosphate transporter broadly expressed in the high-grade serous epithelial ovarian, fallopian tube, and primary peritoneal cancers (OC), with limited expression in normal tissues. UpRi is being evaluated in a Phase Ib/II study (NCT03319628). Methods: The PROC expansion cohort eligibility included patients (pts) with up to four prior lines of therapy. Pts were treated at either 36 or 43mg/m2 up to a maximum (max) dose of ~80mg for pts with body surface area ≥1.8m2, administered intravenously every four weeks. Primary objectives were to evaluate the safety and assess efficacy, including overall response rate (ORR) and disease control rate (DCR) in evaluable pts per RECIST1.1. Tumor tissue was retrospectively evaluated for NaPi2b expression. Results: As of June 10, 2021, 97 pts were enrolled with a median age of 68 (33-87) years; 65 (67%) pts received 1-3 prior lines of therapies, 68 (70%) received prior bevacizumab, and 57 (59%) received prior PARP inhibitor. Of the 78 pts with known NaPi2b score, 64% had high expression based on a Tumor Proportion Score ≥75. This analysis included pts with a lower starting dose of 36mg/m2 (n=12), an intermediate starting dose of approximately 80mg (Pts with BSA ≥1.8m2) (n=46), and a higher starting dose of 43mg/m2 (Pts with BSA ≤1.8m2) (n=39). In the 38 evaluable pts whose tumors were NaPi2b high, confirmed ORR was 34% (13/38), including two CRs, and the median duration of response was five months. In the overall evaluable population, regardless of NaPi2b expression, the confirmed ORR and DCR were 23% (17/75) and 72% (54/75), respectively. Response rates were similar across all dose levels. All 97 pts were included in the safety analysis. Dose reductions and discontinuations due to treatment-related adverse events (TRAEs) were 28% and 10%, respectively. The most frequently reported TRAEs were fatigue, nausea, transient AST increase, thrombocytopenia, and decreased appetite. The most common grade ≥3 events were transient AST increase, fatigue, anemia, and thrombocytopenia. No grade ≥3 (severe) TRAEs of neutropenia, peripheral neuropathy, or ocular toxicity have been reported. Less frequent grade 3+ TRAEs, including pneumonitis, and lower rates of dose reduction and discontinuation were observed in pts treated with the lower dose. Conclusions: UpRi continues to demonstrate encouraging singleagent antitumor activity and a favorable tolerability profile in heavily pretreated pts with OC. UpRi activity was observed in pts previously failing platinum, bevacizumab, and PARP inhibitors. These data support further clinical development of UpRi in a single-arm registrational strategy utilizing 36mg/m2 up to a max dose of approximately 80mg every four weeks (UPLIFT; NCT03319628). Objectives: Effective and well-tolerated treatments for platinum-resistant ovarian cancer (PROC) remain a substantial unmet medical need; single-agent chemotherapy, which is the standard of care, has limited efficacy (response rate ≤12%). Upifitamab Rilsodotin (UpRi) is a first-in-class Dolaflexin ADC targeting NaPi2b, a sodium-dependent phosphate transporter broadly expressed in the high-grade serous epithelial ovarian, fallopian tube, and primary peritoneal cancers (OC), with limited expression in normal tissues. UpRi is being evaluated in a Phase Ib/II study (NCT03319628). Methods: The PROC expansion cohort eligibility included patients (pts) with up to four prior lines of therapy. Pts were treated at either 36 or 43mg/m2 up to a maximum (max) dose of ~80mg for pts with body surface area ≥1.8m2, administered intravenously every four weeks. Primary objectives were to evaluate the safety and assess efficacy, including overall response rate (ORR) and disease control rate (DCR) in evaluable pts per RECIST1.1. Tumor tissue was retrospectively evaluated for NaPi2b expression. Results: As of June 10, 2021, 97 pts were enrolled with a median age of 68 (33-87) years; 65 (67%) pts received 1-3 prior lines of therapies, 68 (70%) received prior bevacizumab, and 57 (59%) received prior PARP inhibitor. Of the 78 pts with known NaPi2b score, 64% had high expression based on a Tumor Proportion Score ≥75. This analysis included pts with a lower starting dose of 36mg/m2 (n=12), an intermediate starting dose of approximately 80mg (Pts with BSA ≥1.8m2) (n=46), and a higher starting dose of 43mg/m2 (Pts with BSA ≤1.8m2) (n=39). In the 38 evaluable pts whose tumors were NaPi2b high, confirmed ORR was 34% (13/38), including two CRs, and the median duration of response was five months. In the overall evaluable population, regardless of NaPi2b expression, the confirmed ORR and DCR were 23% (17/75) and 72% (54/75), respectively. Response rates were similar across all dose levels. All 97 pts were included in the safety analysis. Dose reductions and discontinuations due to treatment-related adverse events (TRAEs) were 28% and 10%, respectively. The most frequently reported TRAEs were fatigue, nausea, transient AST increase, thrombocytopenia, and decreased appetite. The most common grade ≥3 events were transient AST increase, fatigue, anemia, and thrombocytopenia. No grade ≥3 (severe) TRAEs of neutropenia, peripheral neuropathy, or ocular toxicity have been reported. Less frequent grade 3+ TRAEs, including pneumonitis, and lower rates of dose reduction and discontinuation were observed in pts treated with the lower dose. Conclusions: UpRi continues to demonstrate encouraging singleagent antitumor activity and a favorable tolerability profile in heavily pretreated pts with OC. UpRi activity was observed in pts previously failing platinum, bevacizumab, and PARP inhibitors. These data support further clinical development of UpRi in a single-arm registrational strategy utilizing 36mg/m2 up to a max dose of approximately 80mg every four weeks (UPLIFT; NCT03319628).