Farletuzumab/Chemo Fails to Improve PFS in Platinum-Sensitive, Recurrent Ovarian Cancer With Low CA-125

Thomas Herzog, MD

The addition of farletuzumab (MORAb-003) to carboplatin plus paclitaxel or carboplatin plus pegylated liposomal doxorubicin (PLD) did not demonstrate superiority over placebo plus chemotherapy in patients with platinum-sensitive recurrent ovarian cancer who are in their first relapse and have low cancer antigen (CA)-125 levels, according to data from a phase 2 study presented during the 2021 SGO Virtual Annual Meeting on Women’s Cancer.¹

Farletuzumab plus chemotherapy resulted in a median investigator-assessed progression-free survival (PFS) of 11.7 months (95% CI, 10.2-13.6) vs 10.8 months (95% CI, 9.5-13.2) with placebo/chemotherapy (hazard ratio [HR], 0.9; 80% CI, 0.7-1.1; one-sided stratified log rank P = .25). Moreover, the interim median overall survival (OS) had not yet been reached (NR) in the farletuzumab arm (95% CI, 37.1-NR) vs 40.7 months (95% CI, 34.8-NR) in the placebo arm (HR, 1.1; 80% CI, 0.7-1.5; P = .56).

Moreover, patients who were treated with farletuzumab had an overall response rate of 69.6% (95% CI, 61.2-77.1; n = 96) vs 73.5% (95% CI, 61.4-83.5; n = 50) in the placebo arm. Patients in the farletuzumab arm experienced a complete response (CR) rate of 17.4% and a 52.2% partial response (PR) rate vs 22.1% and 51.5%, respectively, in the placebo arm.

“Efficacy data demonstrated no significant differences between treatment groups for any efficacy parameters, including clinical benefit rate, CRs and PRs, as well as stable disease, time to response [TTR], and duration of response [DOR],” Thomas Herzog, MD, a professor of obstetrics and gynecology and deputy director at University of Cincinnati Cancer Institute, said during a presentation on the findings.

Farletuzumab, a humanized monoclonal antibody, binds to folate receptor alpha, which is known to be highly expressed in epithelial ovarian cancer and is associated with the malignant potential of the disease. The agent has previously yielded promising preclinical antitumor activity when evaluated in xenograft ovarian cancer models, and has demonstrated PFS (HR, 0.49) and OS (HR, 0.44) superiority over placebo in patients with ovarian cancer who were in their first platinum sensitive relapse and had low CA-125 in a phase 3 study.²

"The hypothesis is that CA-125 directly binds to farletuzumab, thereby interfering with its complement- and antibody-mediated tumor cellular cytotoxicity,” Herzog explained.

The primary objective of the phase 2 study was to determine whether farletuzumab in addition to carboplatin and paclitaxel or carboplatin plus PLD could demonstrate superiority over placebo in terms of improving PFS in patients with platinum-sensitive ovarian cancer who are in their first relapse and have low CA-125. Additionally, investigators aimed to determine the safety and tolerability of the farletuzumab/chemotherapy combination.

The trial enrolled patients with high-grade serous platinum sensitive recurrent ovarian cancer who experienced their first recurrence 6 to 36 months prior to enrollment on the trial. Additionally, patients were required to have a CA-125 level of less than or equal to 3 times the upper limit of normal (105 U/mL).

Participants were randomized 2:1 to either farletuzumab plus chemotherapy or placebo plus chemotherapy, with stratification factors including platinum-free interval (6 to 12 months vs more than 12 moths) and chemotherapy regimen. Treatment with farletuzumab or placebo occurred during chemotherapy and the maintenance phase of treatment. The primary objective of the study was PFS, with key secondary objectives including safety and tolerability.

"The goal of the study was to improve PFS with the addition of farletuzumab, with a targeted HR of less than 0.667 with an 85% power using a 1-sided type 1 error rate of 0.10,” Herzog said. “The Kaplan-Meier curves for both PFS and OS, TTR, and DOR were compared with stratified log-rank tests. Two-hundred and ten patients were targeted for enrollment.”

A total of 332 patients were screened and 214 were randomly assigned; 211 patients received treatment with either the farletuzumab regimen or placebo regimen. In the experimental arms, 74.6% of patients received PLD (n = 106) and 25.4% (n = 36) received carboplatin and paclitaxel vs 72.2% (n = 52) and 27.8% (n = 20), respectively, in the control group.

Moreover, 21.1% of patients in the farletuzumab arms and 19.4% of patients in the placebo arms discontinued treatment due to progressive disease by RECIST criteria (9.9% vs 8.3%, respectively), adverse effects (AEs; 4.9% vs 4.2%), or patient choice (2.1% vs 4.2%).

Maintenance treatment was initiated in 76.8% and 79.2% of patients in the investigative and control arms, respectively, and it was discontinued in 64.1% and 72.2% of patients, respectively. Of those in the farletuzumab arms, 52.8% discontinued maintenance due to progressive disease by RECIST criteria, 4.2% due to patient choice, and 2.8% because of AEs. Of those in the placebo arms, 62.5% discontinued due to progressive disease by RECIST criteria, 4.2% did so because of clinical progressive disease, and 2.8% because of patient choice.

The median age across both treatment arms was 64.0 years (range, 29-88). Moreover, 27.6% received prior maintenance treatment, 79.9% experienced best response to prior therapy, and the majority (79.0%) had an ECOG performance status of 0. About 42% of patients had a platinum-free interval following first-line therapy of 6 to 12-months, while 58.4% had a 12- to 36-month platinum-free interval. The most common primary tumor site was the ovary (82.7%) followed by fallopian tube (11.2%) and primary peritoneal (5.6%).

Additional data indicated that 26.1% of patients on the farletuzumab arms experienced stable disease versus 25.0% of those enrolled on the placebo arms. Investigators noted a clinical benefit rate of 88.4% and 89.7% in the investigative and control arms, respectively. Patients who received a farletuzumab regimen had a median TTR of 2.69 months (95% CI, 1.7-2.8) and a median DOR of 10.1 months (95% CI, 8.5-11.5); in the placebo arm, these numbers were 2.53 months (95% CI, 1.5-2.7) and 8.5 months (95% CI, 6.3-11.0), respectively.

Treatment-emergent AEs (TEAEs) that were grade 3 or higher occurred in 64.5% of patients who received a farletuzumab regimen and 70.0% of those who were given a placebo regimen. In total, 29.8% and 24.3% of patients in both arms, respectively, experienced serious TEAEs.

The most common TEAEs reported across the investigative and control arms included nausea (68% vs 64%), anemia (54% vs 51%), fatigue (49% vs 50%), and constipation (41% vs 43%). The most notable grade 3/4 TEAEs observed in both arms were neutropenia, anemia, and thrombocytopenia. Five percent of patients in the investigative arms developed interstitial lung disease (ILD) vs none in the placebo arms.

"Is there a future for farletuzumab in ovarian cancer? Perhaps, but not likely as a monoclonal antibody alone,” Herzog concluded. “A derivative compound, MORAb-202 is an antibody-drug conjugate with farletuzumab linked to eribulin as the cytotoxic payload. Promising phase 1 Japanese data have spurred ongoing trials for ovarian, endometrial, and endometrial cancers.”

References

1. Herzog TJ, Pignata S, Ghamande S, et al. A randomized, double-blind, placebo-controlled, phase II study to assess the efficacy/safety of farletuzumab in combination with carboplatin plus paclitaxel or carboplatin plus pegylated liposomal doxorubicin (PLD) in women with low CA125 pl. Presented at: 2021 SGO Virtual Annual Meeting on Women’s Cancer; March 19-21, 2021; Virtual. Accessed March 23, 2021.
2. Vergote I, Armstrong D, Scambia G, et al. A randomized, double-blind, placebo-controlled, phase III study to assess efficacy and safety of weekly farletuzumab in combination with carboplatin and taxane in patients with ovarian cancer in first platinum-sensitive relapse. J Clin Oncol. 2016;34(19):2271-2278. doi:10.1200/JCO.2015.63.2596