FR alpha expression is limited on normal cells, but upregulated on cancers such as ovarian, endometrial, and triple-negative breast cancers.
Targeting folate in oncology is not new, explained Kathleen N. Moore, MD, MS, during a presentation at the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting. Efforts to exploit folates in the pursuit of anti-cancer therapies started with anti-metabolites, such as methotrexate and pemetrexed, according to Moore.
“These efforts focused on mechanisms of folate uptake, including reduced folate carriers [RFC],” she said during the presentation. “More recent efforts have focused on the folate receptor [FR] itself, and specifically FR alpha. Current research is seeking to utilize FR alpha as a therapeutic target, possible CAR-T target, a diagnostic target, and potentially as an imaging modality to improve cytoreduction.”
Specifically, FR alpha has been found to be an ideal target for ovarian cancer, according to Moore. FR alpha is a cell surface folate receptor that mediates folate transport into epithelial cells, and FR alpha expression is limited on normal cells. However, FR alpha expression is upregulated on cancers, such as on endometrial cancers and triple-negative breast cancers (TNBCs), but also primarily on ovarian cancers.
“FR alpha may be expressed on the alveoli of the lungs and on renal proximal tubules. However, these receptors are located on the surface of the cell facing the alveolar and tubular lumen, which reduces the exposure of the targets to circulating anti-folate agents,” Moore said.
Furthermore, FR alpha is overexpressed in 14%-74% of non-small cell lung cancers, in 72%-100% of mesotheliomas, in 20%-50% of endometrial cancers, in 35%-68% of TNBCs, and in 76%-89% of epithelial ovarian cancers. However, FR alpha is expressed in 0%-7% of non-malignant endometrial tissue samples, 0%-20% of non-malignant breast tissue samples, and 0%-25% of non-malignant ovarian tissue samples.
“There are also moderate levels of FR alpha expression, typically restricted to the apical surfaces of bronchial cells, in 75%-90% of tissue samples,” Moore said. “There’s also no detectable FR alpha expression in non-malignant pleural tissue samples.”
Moore also noted that out of 14 antibody drug conjugates (ADCs) currently under evaluation in gynecologic cancers, 3 target FR alpha: mirvetuximab soravtansine (Elahere; ImmunoGen, Inc), STRO-002 luveltamab tazevibulin (Luvelta; Sutro Biopharma), and MORAb-202 (Farletuzumab ecteribulin; Eisai and Bristol Myers Squibb).
For mirvetuximab soravtansine, there are 4 trials underway: the phase 3 Gloriosa trial (NCT05445778), the phase 3 MIRASOL trial (NCT04209855), the phase 2 SORAYA trial (NCT04296890), and the phase 2 PICCOLO trial (NCT05041257). For STRO-002 luveltamab tazevibulin, there are 2 phase 1 trials (NCT03748186 and NCT05200364) underway, and for MORAb-202 there is 1 phase 2 trial being conducted (NCT05613088).
“There's a lot of [ADCs] under development, and [ADCs] are emerging as highly active therapeutics in gynecologic cancers,” Moore said. “Actually, this list [of 14 ADCs] is an incomplete list as of yesterday, but these are most of the [ADCs] that are [under investigation] in phase 2 or 3.”
The ADC targeting FR alpha with the most available data is mirvetuximab soravtansine, which conjugates to DM4, a microtubule toxin. Based on the phase 3 SORAYA trial, the results showed 71% of patients experienced tumor reduction, which was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST; n=102a). During the trial, the most common treatment-related adverse events were blurred vision, keratopathy (a non-inflammatory condition of the eye), and nausea.
“So what are the basics of using mirvetuximab soravtansine and who are eligible? Currently, patients with platinum resistant ovarian cancer—including fallopian tube and peritoneal—who have been on 1 to 3 prior lines of therapy and who show high FR alpha expression by the FDA-approved CDx are eligible,” Moore said.
Moore additionally noted that the starting dose for mirvetuximab soravtansine is 6 mg/kg given intravenous every 3 weeks and should be dosed by adjusted ideal body weight (AIBW). AIBW can be calculated as IBW + 0.25 x (actual weight – IBW), according to Moore.
Furthermore, FR alpha status should be determined by an IHC test; approximately 35% of (mainly serous) tumors are FR alpha and eligible for mirvetuximab soravtansine. Additionally, FR alpha is defined as more than 75% of tumor cells staining with 2+ or 3+ intensity by the VENTANA FOLR1 (FOLR1-2.1) RxDx Assay.
“Mirvetuximab soravtansine is now FDA-approved based on accelerated approval in the United States as of November 2022. Results of the MIRASOL trial will also be released at this ASCO meeting with an anticipated full FDA approval as well as global authorization [to follow],” Moore said. “Mitigation strategies and attention to ocular disorders should allow patients to maintain dosing and benefit from MIRV without permanent ocular impairment.”
Moore KN. New Frontiers in Drug Development: Targeting Folate Receptor Alpha. Presented at 2023 ASCO Annual Meeting; June 2, 2023 in Chicago, IL. Accessed June 2, 2023. https://meetings.asco.org/2023-asco-annual-meeting/15173