Farletuzumab Ecteribulin Shows Early Activity in Platinum-Resistant Ovarian Cancer

The antibody-drug conjugate (ADC) farletuzumab ecteribulin (MORab-202) demonstrated notable antitumor activity with a manageable safety profile in patients with platinum-resistant ovarian cancer, according to data from the dose-expansion portion of the phase 1 Study 101 trial (NCT03386942) presented during the 2022 ASCO Annual Meeting.¹

In cohort 1, which comprised patients who received farletuzumab ecteribulin at 0.9 mg/kg (n = 24), the overall response rate (ORR) was 25.0% (95% CI, 9.8%-46.7%). One patient achieved a complete response, 20.8% experienced a partial response (PR), and 41.7% had stable disease (SD); 33.3% of patients experienced disease progression. The disease control rate (DCR) achieved with the agent in cohort 1 was 66.7% (95% CI, 44.7%-84.4%).

Patients in cohort 2, who received farletuzumab ecteribulin at 1.2 mg/kg (n = 21), achieved an ORR of 52.4% (95% CI, 29.8%-74.3%) with the ADC; this included a PR rate of 52.4%, and a SD rate of 42.9%. One patient in this cohort experienced progressive disease. The DCR was 95.2% (95% CI, 76.2%-99.9%) in this cohort.

“We are encouraged by the clinical safety and efficacy results, as measured by the preliminary antitumor activity observed in patients with platinum-resistant ovarian cancer being treated with each dose of farletuzumab ecteribulin, and with varying levels of folate receptor-alpha [FRα] expression,” Shin Nishio, MD, PhD, lead study author and an associate professor in the Department of Obstetrics and Gynecology at Kurume University School of Medicine in Fukuoka, Japan, stated in a press release.²

Farletuzumab ecteribulin is comprised of the humanized anti-FRα monoclonal antibody, farletuzumab, linked to the cytotoxic microtubule inhibitor, eribulin (Halaven). The ADC delivers the eribulin payload into cancer cells that express FRα.

“Based on the data from preclinical studies, farletuzumab ecteribulin has the clinical potential to elicit a bystander effect through an enzymatically cleavable linker that releases a toxic payload from the antibody, therefore acting not only on the FRα-positive cancer cells, but also the FRα-negative cancer cells surrounding the FRα-positive cancer cells,” Nishio added. “As the field of targeted therapy continues to evolve, ADCs are anticipated to become a key modality in the treatment of recurrent, platinum-resistant disease.”

In the dose-escalation portion of the trial, which was performed in Japan, farletuzumab ecteribulin displayed antitumor activity in patients with FRα-positive solid tumors, including those with ovarian cancer. In that portion of the research, investigators evaluated the ADC at doses ranging from 0.3 mg/kg to 1.2 mg/kg, administered every 3 weeks.³ In 22 patients, 1 patient experienced a CR, 9 had PRs, and 8 had SD. Five of these responses occurred in patients with ovarian cancer.

Based on these findings, investigators selected the 0.9 mg/kg and 1.2 mg/kg doses of the ADC to be examined further in those with platinum-resistant ovarian cancer in the expansion portion of the trial.

Patients with ovarian, fallopian tube, or peritoneal cancer measurable by RECIST v1.1 criteria were enrolled to the dose-expansion portion of the research. To be eligible to enroll, patients were needed to have undergone no more than 2 prior lines of chemotherapy after diagnosis, have an ECOG performance status of 0 or 1, and have adequate organ function. Patients with high-grade serous carcinoma and other histology were required to be FRα positive per central testing.

Patients in cohort 1 were administered 0.9 mg/kg of intravenous (IV) farletuzumab ecteribulin every 3 weeks in the dose-expansion portion of the trial. Following a safety assessment of cohort 1, patients in cohort 2 received 1.2 mg/kg of IV farletuzumab ecteribulin every 3 weeks.

The primary end point of the trial was safety and tolerability. Secondary end points included identifying the recommended phase 2 dose of the ADC, pharmacokinetics, ORR, DCR, and clinical benefit rate. Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) also served as secondary end points for the dose-expansion portion of the trial.

The median age of patients in cohort 1 and cohort 2 was 56 years (range, 23-74) and 58 years (range, 41-76), respectively. All patients in both cohorts were Japanese. Most patients had an ECOG performance status of 0 (75% and 66.7% in cohorts 1 cohort 2, respectively), did not receive any systemic regimens after platinum resistance (62.5% and 66.7%), had ovarian cancer (75.0% and 66.7%), and a FRα expression of at least 50% (75.0% and 90.5%).

Twenty-five percent and 19% of those in cohorts 1 and 2, respectively, received 1 prior anticancer regimen; 25% and 14.3%, respectively, received 2 prior regimens; 20.8% and 38.1%, respectively, received 3 prior regimens; and 29.2% and 28.6%, respectively, received 4 or more.

Additional data showed that patients in cohort 1 who had a FRα expression of at least 50% had an ORR of 22.2% (n = 4/18; 95% CI, 6.4%-47.6%) compared with 33.3% (n = 2/6; 95% CI, 4.3%-77.7%) in those with FRα levels below 50%. In cohort 2, those rates were 52.6% (n = 10/19; 95% CI, 28.9%-75.6%) and 50.0% (n = 1/2; 95% CI, 1.3%-98.7%), respectively.

In cohort 1, patients with high-grade serous carcinoma (n = 19) achieved an ORR of 31.6% (95% CI, 12.6%-56.6%) vs no responses in 5 patients with non–high-grade serous carcinoma. In cohort 2, patients with high-grade serous carcinoma (n = 20) had an ORR of 50% (95% CI, 27.2%-72.8%), vs 100% (95% CI, 2.5%-100%) in 1 patient with non–high-grade serous carcinoma.

The median DOR was 10.6 months (95% CI, 3.9­–not estimable [NE]) and 7.6 months (95% CI, 4.3-10.8) in cohorts 1 and 2, respectively. In cohort 1, the median PFS was 6.7 months (95% CI, 1.5-12.0), and the median OS was 10.5 months (95% CI, 6.4-15.1). In cohort 2, farletuzumab ecteribulin resulted in a median PFS of 8.2 months (95% CI, 4.2-10.4) and a median OS that was NE (95% CI, 12.5-NE).

Regarding safety, 100% and 95.2% of patients in cohorts 1 and 2, respectively, experienced at least 1 treatment-emergent adverse effect (TEAE) of any grade; 33.3% and 28.6% of patients, respectively, had a grade 3 or 4 TEAE.

Common TEAEs of any grade included interstitial lung disease (ILD)/pneumonitis (37.5% and 66.7% in cohort 1 and cohort 2, respectively), pyrexia (33.3% and 42.9%), nausea (25.0% and 33.3%), nasopharyngitis (20.8% and 4.8%), increase alanine aminotransferase levels (20.8% and 19.0%), increased γ-glutamyl transferase (20.8% and 4.8%), malaise (16.7% and 28.6%), headache (12.5% and 47.6%), and diarrhea (12.5% and 23.8%).

Regarding ILD, 8 of 9 cases in cohort 1 were grade 1, and the last case was grade 2. In cohort 2, 6 patients experienced grade 1 ILD, 7 patients had grade 2 ILD, and 1 patient had grade 3 ILD. In cohort 1, ILD events led to discontinuation in 1 patient, dose reduction in 5 patients, and dose interruption in 1 patient. In cohort 2, 5 patients had an ILD event that resulted in discontinuation, 9 had an event that required dose reduction, and 4 had an event that led to dose interruption.

Serious respiratory events were reported in 8.3% and 14.3% of patients in cohorts 1 and 2, respectively.

After data cutoff, 1 patient in cohort 1 died and was considered to have an unspecified lung disorder related to treatment. It was retrospectively noted that the patient had evidence of ILD on a prior CT scan. The patient had no respiratory symptoms prior to death and received 32 cycles of treatment with farletuzumab ecteribulin.

Bone marrow suppression—indicated by neutropenia, anemia, and leukopenia—was mostly low grade. Among all patients, non-serious TEAEs in the form of neutropenia, anemia, and leukopenia were reported in 4.4%, 8.9%, and 2.2%, of patients, respectively. Only 2 cases of grade 3 anemia were reported, and this occurred in 1 patient in each cohort.

References

1. Nishio S, Yunokawa M, Matsumoto K, et al. Safety and efficacy of MORAb-202 in patients with platinum-resistant ovarian cancer (PROC): results from the expansion part of a phase 1 trial. J Clin Oncol. 2022;40(suppl 16):5513. doi:10.1200/JCO.2022.40.16_suppl.5513
2. Eisai presents new findings for antibody drug conjugate farletuzumab ecteribulin at 2022 ASCO Annual Meeting. News release. Eisai Co., Ltd. June 6, 2022. Accessed June 20, 2022. https://bit.ly/3b3ERmG
3. Shimizu T, Fujiwara Y, Yonemori K, et al. First-in-human phase 1 study of MORAb-202, an antibody-drug conjugate comprising farletuzumab linked to eribulin mesylate, in patients with folate receptor-α-positive advanced tumors. Clin Cancer Res. 2021;27(14):3905-3915. doi:10.1158/1078-0432.CCR-20-4740