Thomas J. Herzog, MD
Professor of Obstetrics and Gynecology
University of Cincinnati Cancer Institute
Randomized Phase II Placebo-Controlled Trial with Farletuzumab (FAR) or Placebo Plus Carboplatin/Paclitaxel or Carboplatin/Pegylated Liposomal Doxorubicin in Low CA-125 Platinum-Sensitive Ovarian Cancer
Herzog TJ. SGO Annual Meeting, Oral Scientific Plenary, 2021.
Farletuzumab in Platinum Sensitive Ovarian Cancer: A Randomized Phase II Placebo-Controlled Trial with Farletuzumab or Placebo with Carboplatin/Paclitaxel or Carboplatin/Pegylated Liposomal Doxorubicin in Patients with Low CA-125 levels
Recurrent ovarian cancer continues to be a challenging disease as survival has modestly improved over the past two decades largely from incremental improvements from progression free survival (PFS) gains from multiple active therapies that are sequenced. Despite advancements in therapy, novel agents are needed to improve outcomes.
Farletuzumab Is a humanized IgG1 monoclonal antibody that binds the folate receptor-alpha, which is expressed in approximately 80% of patients with epithelial ovarian cancer. Folate receptor-alpha, a glycosylphosphatidylinositol anchored membrane protein, is a rationale target of antibody , as it is largely absent from normal tissues but is overexpressed in malignant tumors of epithelial origin, including ovarian, lung, and breast cancer. Furthermore, there are data suggesting folate receptor-alpha expression is associated with poor prognosis. There is preclinical data to support the use of farletuzumab in recurrent ovarian cancer. Moreover, there was a pre-specified subset analysis of a phase III trial that compared farletuzumab versus placebo in platinum sensitive recurrent ovarian cancer (PSROC) reported by Vergote et. al. in 2016 that demonstrated impressive PFS and overall survival (OS) data with hazard ratios (HR’s) < 0.5 for both endpoints in the cohort of patients with low Ca-125 levels.
The hypothesis behind the theory that efficacy with this monoclonal antibody may be improved in patients who have low Ca-125 levels is based upon the observation that Ca-125 directly binds to farletuzumab. This binding in turns interferes with its complement and antibody mediated tumor cellular cytotoxicity.
The objectives of this randomized phase II trial were to determine if farletuzumab added to one of two platinum-based chemotherapy regimens with either platinum and paclitaxel or platinum and pegylated liposomal doxorubicin improved PFS in patients experiencing their first-relapse and classified as PSROC patients with low CA-125 levels would benefit from farletuzumab or not. Low levels for this tumor antigen were defined as < 3 times the upper limits of normal, thus a value of 105 or less was required for many assays. Safety and tolerability of farletuzumab was also assessed.
Eligible patients demonstrated high-grade serous platinum sensitive recurrent ovarian cancer
with first recurrence within 6 to 36 months prior, and the Ca-125 antigen was ≤3 x upper limits of normal (105 U/mL). Patients were required to have an ECOG performance status of 0-2. Stratification factors for this trial included platinum-free interval of 6 to 12 months versus greater than 12 months, and chemotherapy regimen with platinum with paclitaxel versus platinum with pegylated liposomal doxorubicin.
The study used a 2:1 randomization to farletuzumab versus placebo. Treatment with farletuzumab or placebo occurred during chemotherapy and as maintenance therapy as well.
The statistical analysis plan described the goal of reducing the risk of progression or death by 33% in the experimental arms, thus a HR < 0.67 was targeted for the farletuzumab cohort with 85% power with a 1-sided type I error rate of 0.1. Kaplan Meir curves for both PFS and OS, time to response, and duration of response were generated and compared for significance with a stratified log-rank test. A total of 210 patients were targeted for enrollment.
There were 332 patients screened in order to treat 211 patients who were randomized 2:1 to farletuzumab with just under 75% receiving platinum and paclitaxel versus pegylated liposomal per Investigator choice. Approximately 78% of patients went on to receive maintenance therapy with no significant difference as assessed by farletuzumab versus placebo assignment. The principle reason for discontinuation from this clinical trial was progression of disease.
Patient demographics such as performance status, prior response to therapy, primary site of origin of tumor, and other key prognostic factors were well balanced between the two primary cohorts of chemotherapy farletuzumab versus placebo. Notably, 58% of patients had a platinum free interval of 12 to 36 months.
Efficacy data demonstrated that there was no significant difference between treatment groups for any efficacy parameters including clinical benefit rate, time to response, duration of response, or lengthening of the second platinum-free interval. The overall response rate was 70% for farletuzumab versus 74% for placebo. The duration of response (DOR) was 10.1 months for those treated with farletuzumab versus 8.5 months in the placebo group.
There was no difference between cohorts for the primary endpoint with median investigator PFS of 11.7 months for treatment with farletuzumab vs. 10.8 months for placebo. HR was 0.9 with 80% confidence interval of 0.7 to 1.1 (p value = 0.25). Interim OS demonstrated no significant differences between cohorts either.
Treatment emergent adverse events (TEAEs) during the entire study were comparable in both treatment groups with most frequent being nausea, anemia, fatigue and constipation.
The incidence of TEAEs ≥ grade 3 overall was similar across the two treatment groups; 65% in the farletuzumab + chemotherapy group vs. 70.0% in the placebo + chemotherapy group.
The incidence of treatment-emergent serious adverse events was similar between the two treatment groups with 30% observed in farletuzumab versus 24% for the placebo group.
Interestingly, interstitial lung disease was observed in 7 patients (5.0%) treated with farletuzumab versus none in the placebo group.
The authors concluded that the combination of chemotherapy and farletuzumab did not show superior efficacy compared with conventional chemotherapy in improving PFS or other efficacy parameters in patients with PSROC in first relapse who had low CA-125 levels. No new significant safety signals were observed.
So the question becomes is there a future for farletuzumab in the treatment of ovarian cancer? The answer is that likely efficacy is not sufficient to warrant further development currently as the monoclonal antibody alone; however, recent focus on antibody-drug conjugates (ADCs), may provide a rational pathway forward as a promising cancer therapeutic based on the farletuzumab backbone. Specifically, a derivative known as MORAb-202 is an ADC with farletuzumab with a cleavable linkage to an erubulin cytotoxic payload. A phase I Japanese study demonstrated promising results with a 45% overall response rate including a complete response in a patient with ovarian cancer. Ongoing studies are planned that include ovarian and endometrial cancer patients to see if the folate receptor alpha target of farletuzumab is active when combined with a direct cytotoxic.
1] Vergote I, Armstrong D, Scambia G, Teneriello M, Sehouli J, Schweizer C, Weil SC, Bamias A, Fujiwara K, Ochiai K, Poole C, Gorbunova V, Wang W, O'Shannessy D, Herzog TJ. 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 Jul 1;34(19):2271-8. doi: 10.1200/JCO.2015.63.2596. Epub 2016 Mar 21.PMID: 27001568
2] Herzog TJ, Pignata S, Ghamande S, Rubio MJ, Fujiwara K, Vulsteke C, Armstrong DK, Sehouli J, Coleman RL, Gabra H, Scambia G, Monk BJ, Arranz JA, Ushijima K, Hanna R, Zamagni C, Wenham RM, Gonzalez-Martin A, Slomovitz B, Jia Y, Ramsay L, Tewari KS, Weil SC, Vergote I; Randomized Phase II Placebo-Controlled Trial with Farletuzumab (FAR) or Placebo Plus Carboplatin/Paclitaxel or Carboplatin/Pegylated Liposomal Doxorubicin in Low CA-125
Platinum-Sensitive Ovarian Cancer; SGO Annual Meeting, Oral Scientific Plenary, 2021
3] Sato J., Shimizu T., Fujiwara Y., Yonemori K., Koyama T., Shimomura A., Tamura K., Iwasa S., Kondo S., Sudo K., Ikezawa H., Nomoto M., Nakajima R., Miura T., Yamamoto, N.; Annals of Oncology; ESMO 2020. Volume 31, Supplement 1S1-S14.