Monotherapy with torvutatug samrotecan (AZD5335; Torvu-Sam), an FRα-targeted antibody-drug conjugate (ADC), demonstrated antitumor activity across the spectrum of folate receptor α (FRα) expression, including FRα-ultralow or -null tumors, in patients with platinum-resistant ovarian cancer, according to updated results from the phase 1/2a FONTANA trial (NCT05797168) presented at the
Among patients in the dose-optimization portion of the trial, the overall response rate (ORR) was 61.7% (95% CI, 48.2%-73.9%) in those with FRα-high tumors who received torvu-sam (n = 60) and 57.1% (95% CI, 44.0%-69.5%) in those with FRα-low tumors (n = 63). In the dose-expansion cohort of patients with FRα-ultralow or -null tumors, the ORR was 48.1% (95% CI, 28.7%-68.1%) among response-evaluable patients (n = 27).
Moreover, the median duration of response (DOR) was 10.2 months (95% CI, 6.5-10.9) among responders with FRα-high tumors (n = 37) and 8.3 months (95% CI, 6.2-10.6) among responders with FRα-low tumors (n = 36). The median progression-free survival (PFS) was 9.7 months (95% CI, 8.0-12.6) in the overall FRα-high group and 7.6 months (95% CI, 6.0-9.7) in the overall FRα-low group.
“We have a bunch of updates from [ADCs] in ovarian cancer, including the phase 1/2a FONTANA trial [NCT05797168], looking at [torvutatug samrotecan], which is a folate receptor–targeted [ADC],” said Shannon N. Westin, MD, MPH, FASCO, FACOG, in an exclusive interview with OncLive® ahead of the conference.2
Westin is a service line co-lead, professor, clinical medical director, director of Early Drug Development in Gynecologic Oncology and Reproductive Medicine, as well as project leader and co-chair of the Executive Scientific Review Committee, all at The University of Texas MD Anderson Cancer Center in Houston.
The dose optimization part of the first-in-human, open-label study enrolled patients whose tumors expressed FRα in at least 25% of tumor cells at or those with membrane intensity of 1+ or higher by immunohistochemistry. Enrollment criteria for both phases of parts trial required patients to be at least 18 years of age, have an ECOG performance status of 1 or less, histologically confirmed platinum-resistant ovarian cancer, measurable disease per RECIST 1.1 criteria, and at least 3 prior lines of therapy.
The dose expansion portion of the trial enrolled patients with FRα-ultralow or -null tumors, defined as expression in fewer than 25% of tumor cells (n = 32).
Patients were randomly assigned to receive intravenous torvu-sam at 2.4 mg/kg, 2.0 mg/kg, or 1.6 mg/kg every 3 weeks.
The primary end points were safety and tolerability, with secondary end points including ORR, DOR, PFS, and pharmacokinetics, and plasma circulating tumor DNA (ctDNA) assessment was an exploratory end point.
Across the dose optimization portion and the additional dose expansion portion (n = 156), patients had a median age was 64 years (range, 26-82), 53.2% of patients had an ECOG performance status of 1, and the median number of prior lines of therapy was 2.0 (range, 1-4).
Prior therapies included bevacizumab (Avastin) in 67.9% of patients, a PARP inhibitor in 60.3%, and mirvetuximab soravtansine-gynx (Elahere) in 2.6%. The median follow-up was 15.3 months (range, 1.0-24.2) in the dose optimization portion of the trial and 4.8 months (range, 0.4-15.2) in additional dose expansion part of the trial.
The safety analysis included patients treated in the Part A dose escalation, optimization and expansion parts of the trial at 1.6 mg/kg of torvu-sam (n = 53), 2.0 mg/kg (n = 90), and 2.4 mg/kg (n = 64), with median exposure of 10.3 months, 5.6 months, and 8.1 months, respectively.
All patients experienced at least 1 treatment-emergent adverse effect (TEAE) of any grade. Grade 3 or higher TEAEs occurred in 45.3%, 60.0%, and 82.8% of patients at the 1.6-mg/kg, 2.0-mg/kg, and 2.4-mg/kg dose levels, respectively/ Serious TEAEs occurred in 34.0%, 26.7%, and 53.1% of patients treated at each respective dose level. Additionally, TEAEs led to dose reductions in 13.2%, 18.9%, and 48.4% of patients and to discontinuation in 5.7%, 4.4%, and 14.1% at each dose level. One TEAE led to death at each of the 2.0-mg/kg and 2.4-mg/kg doses/
The most common TEAEs across dose levels included nausea, fatigue, neutropenia, anemia, and vomiting, with grade 3 or higher neutropenia and anemia more frequent at 2.4 mg/kg.
Among patients with detectable ctDNA at baseline who were evaluable at cycle 3 day 1 (n = 102), the complete molecular response rate (cMR was 47%, and the rate of any molecular response, was 87%. cMR and any-MR rates were 62% and 77%, respectively, in the FRα-ultralow/null group (n = 13); 43% and 89% in the FRα-low group (n = 46); and 47% and 88% in the FRα-high group (n = 43).
Data from FONTANA supported the design of 3 phase 3 trials. The phase 3 TREVI-OC-01 trial (NCT07218809) which is comparing torvu-sam vs mirvetuximab soravtansine in FRα-high platinum-resistant ovarian cancer and torvu-sam vs chemotherapy in FRα-low platinum-resistant ovarian cancer. The phase 3 TREVI-OC-02 trial (NCT07851025) is evaluating torvu-sam plus bevacizumab as first-line maintenance therapy in homologous recombination deficiency–negative epithelial ovarian cancer, and finally the phase 3 TREVI-OC-03 trial (NCT07816666) which evaluating torvu-sam with or without bevacizumab as maintenance therapy in platinum-resistant ovarian cancer.
