XMT-1536 is a first-in-class dolaflexin platform-designed antibody-drug conjugate that targets the sodium-phosphate cotransporter NaPi2b, which is commonly expressed in solid tumors such as ovarian cancer, among others. XMT-1536 is being studied in a multicenter study of 47 patients with platinum-resistant ovarian cancer and other tumors known to express NaPi2b. The first phase was a dose-escalation study followed by an expansion phase. This is a report on the interim safety and efficacy of XMT-1536 in patients with ovarian cancer in the expansion portion of the ongoing phase 1 study.
Patients in the study have high-grade serous ovarian, fallopian tube, or primary peritoneal cancer and had progressed on ≤3 prior lines of therapy if platinum resistant or ≤4 lines of therapy regardless of platinum sensitivity status. Patients had measurable disease and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Patients received XMT-1536 36 mg/m2 or 43 mg/m2 intravenously once every 4 weeks until disease progression or unacceptable toxicity. Response is being assessed via tumor imaging at baseline and at every second treatment cycle. The primary end points are the safety and tolerability of the maximum tolerated dose and efficacy assessed by overall response rate (ORR) and disease control rate (DCR), as well as retrospective tumor sample assessment for NaPi2b expression.
The data provided in the interim analysis is based on completed assessments of 47 patients. The median age of the patients enrolled is 69 years, 34% (16) of patients had an ECOG PS score of 0 and 66% (31) had an ECOG PS score of 1. Approximately 60% (28) of patients were platinum-resistant and had undergone between 1 and 3 prior lines of therapy, and 40% (19) had undergone 4 prior lines of therapy regardless of platinum sensitivity status, which included bevacizumab in 70% (33) of patients and poly (ADP-ribose) polymerase (PARP) inhibitors in 53% (25) of patients. The platinum-free interval was 0 to 3 months in 30% of enrolled patients, >3 to 6 months in 57%, >6 months in 11%, and unknown in 1 patient. The BRCA biomarker status of the patients reflects that 13% have a BRCA1/2 mutation, while such status is unknown in 9% of patients. Using a multiparametric, semiquantitative immunohistochemistry scoring system, the NaPi2b “Histo” (H)-score is higher in 55% of enrolled patients and undetermined in 13% of patients.
The ORR among 29 evaluable patients was 34% (10); ORR was 35% and 29% in the higher and lower NaPi2b H-score groups, respectively. DCR was 79% (23) in the overall population and 85% and 57% in the higher and lower NaPi2b H-score groups, respectively. Response was observed within 2 cycles of XMT-1536 therapy in 70% of patients and within 4 cycles in 100% of evaluable patients. Antitumor activity was positively correlated with a higher level of NaPi2b expression, and duration of response has not been reached in patients with a higher NaPi2b H-score (n = 7). Approximately 50% of the patients with a higher level of NaPi2b expression, 33% of patients with a lower level of NaPi2b expression, and 6 patients in which the NaPi2b expression level is unknown are still receiving treatment.
At least 1 treatment-related adverse event (any grade) was reported by 81% of patients, and 23% of patients required a dose reduction, delay, and/or discontinuation. The most frequently reported treatment-related adverse events were fatigue, nausea, decreased appetite, vomiting, transient increase in aspartate aminotransferase, diarrhea, and thrombocytopenia. No grade ≥3 neutropenia, peripheral neuropathy, or ocular toxicity have been reported.
The results of this interim review support the safety and tolerability of XMT-1536 for patients with relapsing advanced ovarian cancer, and suggest that NaPi2b may be a biomarker of response to XMT-1536.
Abstract and Poster 836P. ESMO 2020. September 19-21, 2020. Safety and efficacy of XMT-1536 in ovarian cancer: a subgroup analysis from the phase 1 expansion study of XMT-1536, a NaPi2b antibody-drug conjugate.