Folate Receptor Alpha Expression Research Articles

Variability of folate receptor alpha expression by race among recurrent ovarian cancer patients

Variability of folate receptor alpha expression by race among recurrent ovarian cancer patients

718MO Mirvetuximab soravtansine (MIRV) in recurrent platinum-sensitive ovarian cancer (PSOC) with high folate receptor-alpha (FRα) expression: Results from the PICCOLO trial

718MO Mirvetuximab soravtansine (MIRV) in recurrent platinum-sensitive ovarian cancer (PSOC) with high folate receptor-alpha (FRα) expression: Results from the PICCOLO trial

746P Phase III MIRASOL trial: Updated overall survival results of mirvetuximab soravtansine (MIRV) vs. investigator’s choice chemotherapy (ICC) in patients (pts) with platinum-resistant ovarian cancer (PROC) and high folate receptor-alpha (FRα) expression

746P Phase III MIRASOL trial: Updated overall survival results of mirvetuximab soravtansine (MIRV) vs. investigator’s choice chemotherapy (ICC) in patients (pts) with platinum-resistant ovarian cancer (PROC) and high folate receptor-alpha (FRα) expression

Folate receptor alpha expression in low-grade serous ovarian cancer: Exploring new therapeutic possibilities

ObjectiveMirvetuximab soravtansine may be a potentially effective therapeutic option for ovarian low-grade serous carcinoma (LGSC), but the prevalence of folate receptor alpha (FRα) overexpression in this tumor type is unknown. We sought to characterize FRα expression in LGSC and its association with clinical and molecular features. MethodsFRα immunohistochemistry was performed on a tissue microarray comprised of 89 LGSCs and 42 ovarian serous borderline tumors (SBTs). Clinical tumor-normal panel-based sequencing was performed on 78 LGSCs. Associations between FRα-high status and clinicopathologic characteristics and survival outcomes were examined. ResultsOf 89 LGSCs, 36 (40%) were FRα-high (≥75% of viable tumor cells exhibiting moderate-to-strong membranous expression). Of 9 patients with LGSC and samples from different timepoints, 4 (44%) had discordant results, with conversion from FRα-negative to FRα-high in 3 (33%) cases. There was no association between FRα-high status with age, race, or progression-free/overall survival. A MAPK pathway genetic alteration, most commonly involving KRAS (n = 23), was present in 45 (58%) LGSCs. Those lacking MAPK pathway alterations were more likely to be FRα-high compared to MAPK-altered LGSCs (61% vs 20%, p < 0.001). In SBTs, FRα-high expression was associated with high-risk (micropapillary) histology and/or subsequent LGSC recurrence compared to conventional SBTs without malignant recurrence (53% vs 9%, p = 0.008). ConclusionsFuture studies of FRα-directed therapy in patients with LGSC are warranted. Discordant FRα status at recurrence suggests potential benefit for retesting. A biomarker-driven approach to direct treatment selection in LGSC is recommended. As high FRα expression is more common amongst tumors lacking MAPK pathway genetic alterations, FRα testing to determine eligibility for mirvetuximab soravtansine therapy is particularly recommended for this subgroup.

Folate Receptor Alpha Expression and the Tumor Immune Microenvironment in Patients with Cervical Cancer.

Folate receptor α (FRα) is a cell-surface protein and an attractive target for cancer treatment. We investigated the association between FRα expression and the tumor immune microenvironment in patients with cervical cancer. We examined whole tumor sections of 123 patients with cervical cancer: 67 and 56 sections of squamous cell carcinoma (SCC) and non-SCC, respectively. FRα expression was assessed using immunohistochemical staining with the anti-FRα monoclonal antibody clone 26B3. Programmed death-ligand 1 (PD-L1) expression was assessed using a combined positive score (CPS). The intratumoral CD3 and CD8 cell densities were calculated as the average number of positive cells in five independent areas. FRα-positivity was identified in 72.4% of the patients, and it differed by histology (SCC vs. non-SCC; 55.2% vs. 92.9%, P<0.001). PD-L1 status was positive (CPS ≥1) in 75.6% and was more commonly expressed in patients with SCC (SCC vs. non-SCC; 83.5% vs. 66.1%, P=0.02). FRα expression had a weak correlation with PD-L1 expression (r=-0.22, P<0.001) and CD8-positive cells (r=-0.19, P=0.03). FRα-positivity was more frequently observed in the PD-L1 CPS <10 group than in the PD-L1 CPS ≥10 group (81% vs. 64%, P=0.03). FRα-high was significantly associated with poor prognosis, especially in the PD-L1 CPS ≥10 groups (hazard ratio: 4.10, 95% confidence interval: 1.39-12.06, P=0.01). In conclusion, FRα expression was higher in patients with cervical cancer and PD-L1 CPS <10 than in those with CPS ≥10. Targeting FRα expression may be a potential therapeutic strategy for cervical cancer patients with low or negative PD-L1 expression.

44O Safety and efficacy results in patients who received dose modifications in the phase III MIRASOL (GOG 3045/ENGOT-ov55) trial of mirvetuximab soravtansine vs investigator’s choice chemotherapy (ICC) in platinum-resistant ovarian cancer (PROC) with high folate receptor-alpha expression

44O Safety and efficacy results in patients who received dose modifications in the phase III MIRASOL (GOG 3045/ENGOT-ov55) trial of mirvetuximab soravtansine vs investigator’s choice chemotherapy (ICC) in platinum-resistant ovarian cancer (PROC) with high folate receptor-alpha expression

Abstract CT008: A phase 2, two-stage study of mirvetuximab soravtansine (IMGN853) in combination with pembrolizumab in patients with microsatellite stable (MSS) recurrent or persistent endometrial cancer

Abstract Background &amp; Objectives: Folate receptor-alpha (FRα) expression is associated with poor prognosis in endometrial cancer (EC). Mirvetuximab soravtansine (MIRV), an antibody drug conjugate (ADC) comprising a FRα-binding antibody, cleavable linker, and the tubulin-disrupting maytansinoid DM4, showed tolerability and single agent activity in a Phase 1 dose expansion study in FRα-positive advanced/recurrent EC (NCT01609556). In addition to target-mediated cytotoxicity, MIRV activates monocytes and promotes phagocytosis of tumor cells through Fc-FcγR interactions. We therefore hypothesized that MIRV would improve the low response to immune checkpoint inhibitors (ICI) in MSS/pMMR EC and conducted this two-stage, phase 2, single cohort study evaluating the activity of MIRV in combination with pembrolizumab in patients with recurrent/persistent EC (NCT03835819). Methods: Patients with advanced or recurrent MSS/pMMR, FRα positive (defined as ≥50% of tumor cells with ≥2+ staining on IHC by Ventana, Inc.) serous EC received MIRV 6 mg/kg AIBW and pembrolizumab 200 mg every 21 days until disease progression or unacceptable toxicity. Patients could have received 1-3 prior lines of therapy; prior ICI therapy was allowed. The co-primary endpoints were objective response rate (ORR) as measured by RECIST 1.1 and frequency of patients surviving progression-free for 6 months (PFS6). In the first stage of the study, 16 patients were enrolled; if there were ≥2 objective responses or ≥2 PFS6 responses, an additional 19 patients would be enrolled in Stage 2. If a total of 4 objective responses or 8 PFS6 events were achieved, the combination would be considered worthy of further study. Data: Among 130 patient tumors prescreened for FRα expression, the median FRα (% of tumor cells with ≥2+ staining) was 30% (IQR: 5-55) and 43 (33.1%) were FRα positive (PS 2+ ≥50%). As of data-cutoff in November 2023, a total of 16 patients had received study treatment with median follow-up of 4.7 months (IQR 2.9, 17.3). Of 16 treated patients, 6 patients (37.5%, 95% CI: 15.2-64.6%) achieved an objective response, including 1 patient achieving a confirmed CR and 5 patients achieving a PR [3 confirmed PR (18.8%) and 2 unconfirmed PR (12.5%)] (Fig. 1). An additional 31.3% (5/16) had stable disease and two patients were alive and progression free at 6 months. The most common TRAEs included AST elevation (50%), blurred vision (44%), fatigue (44%) and diarrhea (43%); grade 3 TRAEs occurred in 2 patients (12.5%). Ocular toxicities of any grade were reported in 56.3% of patients. Updated efficacy and safety data as well as ongoing correlative studies will be reported at the time of the meeting. Conclusions: In this investigator-initiated study, the combination of MIRV and pembrolizumab met the co-primary endpoint to be considered worthy of further study in FRα-positive recurrent MSS/pMMR serous EC. Investigations into subpopulations most likely to derive clinical benefit from this combination are ongoing. Citation Format: Rebecca L. Porter, Niya Xiong, Nabihah Tayob, Madeline Polak, Hannah Sawyer, Martin Hayes, Jeanette Gardner, Susana Campos, Neil Horowitz, Carolyn Krasner, Elizabeth K. Lee, Joyce F. Liu, Elizabeth H. Stover, Jennifer Veneris, Alexi A. Wright, Ursula A. Matulonis, Panagiotis Konstantinopoulos. A phase 2, two-stage study of mirvetuximab soravtansine (IMGN853) in combination with pembrolizumab in patients with microsatellite stable (MSS) recurrent or persistent endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT008.

Histology and Lung Nodule Fluorescence in Intraoperative Molecular Imaging With Pafolacianine

BackgroundIntraoperative molecular imaging (IMI) uses a cancer-targeted fluorescent agent injected into patients to localize tumor nodules. Pafolacianine is a folate receptor (FR)–targeted near-infrared fluorescent probe. Almost 10% of patients have false negative fluorescence findings intraoperatively. We hypothesized that tumor histology explains why lung cancer may not fluoresce. MethodsAdenocarcinoma (AC) (A549, LKR) and squamous cell carcinoma (SCC) (H127, H1264) cell lines were stained with pafolacianine. Near-infrared fluorescent microscopy was used to quantify mean fluorescence intensity. Tissue microarray slides of patients with AC and SCC were evaluated by immunohistochemistry for FR alpha (FRα) and beta (FRβ) expression. Finally, we retrospectively analyzed IMI data from clinical trials of patients with AC and SCC receiving pafolacianine. ResultsAC (intensity 30.31) cell lines have a higher fluorescence intensity than SCC cell lines (intensity 5.4) (P < .001). On slide analysis, 93.8% of ACs expressed FRα compared with 44.4% of SCCs (P = .002). Finally, there were 326 patients enrolled in clinical trials: 211 had lesions localized in vivo, and 134 of these patients had pure AC or SCC. All 9 patients with SCC have a positive smoking history and a mean pack-year of 60.2 (SD 3,6), whereas 76% of patients with AC have a history of smoking and a mean pack-year of 29.3 (P = .02). The odds ratio for fluorescence of (AC/SCC) was 2.05 (P = .004) and 2.01 (P = .02) on univariate and multivariate logistic regression, respectively. ConclusionsDuring IMI with pafolacianine, a nonfluorescent nodule is more likely to be SCC than AC. AC has a high probability of fluorescing because of higher expression of FRα or FRβ, or both.

Abstract B013: Folate receptor alpha (FRa) expression and correlation with other molecular alterations in high grade serous endometrial cancer (EC)

Abstract Background: Advanced and recurrent EC remains a therapeutic challenge with rising mortality rates and few options beyond first line platinum-based chemotherapy and immunotherapy. Mirvetuximab soravtansine (MIRV), an antibody drug conjugate (ADC) comprising a FRα-binding antibody, cleavable linker, and maytansinoid payload DM4, is FDA-approved for patients with FRa-high platinum resistant ovarian cancer (PROC). FRa is also expressed in EC and is associated with poor prognosis. Here, we evaluate FRa expression levels and associations with other molecular alterations, including in HER2, MYC and CCNE1, in patients with advanced/recurrent serous EC. Methods: Paraffin fixed tumor tissue from 110 patients who signed prescreening consent for a phase 2 study testing the combination of MIRV with pembrolizumab in recurrent/persistent serous EC (NCT03835819) were analyzed for FRα expression by IHC (Ventana, Inc). All patients had advanced or recurrent MSS serous EC and had received 1-3 prior lines of therapy. FRα positivity was defined as ≥50% of cells with ≥2+ membrane staining based on results from a phase 1b study of mirv and pembrolizumab in PROC (Matulonis U, SGO 2018 abstract 74). HER2/neu expression was assessed by independent pathology review at the treating institution. Tumor mutational burden (TMB), amplification of CCNE1, MYC and ERBB2 and other somatic mutations were determined in tumors with next generation sequencing (NGS). Results: 37 of 110 tumors were determined to be FRa positive (FRa+) with FRa ≥50% for an overall positivity rate of 33.63%. The median membrane positivity was 20.5% (IQR: 3-51.25). Within a cohort of 44 patients with available tumor NGS, the average TMB was 6.23 (SD: 3.34) and did not differ between FRα+ and -negative (FRα-) tumors at 5.74 and 6.45, respectively (p=0.73). Of 32 tumors with HER2 IHC performed, 5 (16%) were both FRα+ and HER2+ (2+ or 3+); 7 (22%) were FRα+ and HER2-, 5 (16%) were FRα- and HER2+, and 15 (47%) had negative expression for both. CCNE1, MYC and ERBB2 amplifications were present in 1 (9%), 0 and 3 (27%) of FRα+ tumors, and 6 (23%), (8) 31%, and 2 (8%) and of FRα- tumors, respectively. There was no association between expression of FRα and HER2 (Fisher exact test, p=0.44), nor with amplification of CCNE1 (p=0.65), MYC (p=0.08) and ERBB2 (p=0.14). The most common co-occurring somatic mutations were in PIK3CA, with similar frequency in FRα+ (55%) and FRα- (42%) tumors. Conclusions: An FRα positivity rate of 33.6% in this large cohort of serous EC tumors supports further clinical development of MIRV in this high-risk subtype of EC. Within a limited cohort subset, it does not appear that FRα expression correlates with TMB or HER2 expression, or with CCNE1, MYC or ERBB2 amplifications. This data highlights the importance of comprehensive testing of EC tumors for all relevant biomarkers that may guide selection of targeted therapies. Additional studies are needed to explore FRα expression in other molecular subsets of EC and to determine the longitudinal stability of ADC target expression. Citation Format: Rebecca L. Porter, Sandy Elias, Niya Xiong, Madeline Polak, Kayla Fahey, Nabihah Tayob, Courtney Qi, Carina Feeney, Swati Narayan, Jennifer Curtis, Susana Campos, Carolyn Krasner, Elizabeth Lee, Elizabeth Stover, Alexi A. Wright, Joyce F. Liu, Ursula A. Matulonis, Panagiotis Konstantinopoulos. Folate receptor alpha (FRa) expression and correlation with other molecular alterations in high grade serous endometrial cancer (EC) [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B013.

Mirvetuximab soravtansine in platinum-resistant recurrent ovarian cancer with high folate receptor-alpha expression: a cost-effectiveness analysis.

Mirvetuximab soravtansine (MIRV), a new antibody-drug conjugate, versus the investigator's choice of chemotherapy (IC) was the first treatment to demonstrate benefits for progression-free and overall survival in platinum-resistant recurrent ovarian cancer (PROC) with high folate receptor-alpha (high-FRα) expression. Efficacy, safety, and economic effectiveness make MIRV the new standard of care for these patients. Based on patients and clinical parameters from MIRASOL (GOG 3045/ENGOT-ov55) phase III randomized controlled trials, the Markov model with a 20-year time horizon was established to evaluate the cost and efficacy of MIRV and IC for PROC with high-FRα expression, considering the bevacizumab-pretreated situation from the American healthcare system. Total cost, life-years (LYs), quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), and incremental net health benefits were the main outcome indicators and compared with willingness-to-pay threshold of $100,000/QALY. Sensitivity and scenario analyses were conducted. Compared with the IC, MIRV was associated with incremental costs of $538,251, $575,674, and $188,248 with the corresponding QALYs (LYs) increased by 0.90 (1.55), 1.09 (1.88), and 0.53 (0.79), leading to ICERs of $596,189/QALY ($347,995/LY), $530,061/QALY ($306,894/LY), and $1,011,310/QALY ($680,025/LY) in the overall, bevacizumab-naïve, and bevacizumab-pretreated patients, respectively. When MIRV is reduced by more than 75%, it may be a cost-effective treatment. At the current price, MIRV for PROC with high-FRα expression is not the cost-effective strategy in the US. However, its treatment has higher health benefits in bevacizumab-naïve patients, which is likely to be an alternative.

Low-dose daily folic acid (400 μg) supplementation does not affect regulation of folate transporters found present throughout the terminal ileum and colon of humans: a randomized clinical trial

BackgroundFolic acid supplementation during the periconceptional period reduces the risk of neural tube defects in infants, but concern over chronic folic acid exposure remains. An improved understanding of folate absorption may clarify potential risks. Folate transporters have been characterized in the small intestine, but less so in the colon of healthy, free-living humans. The impact of folic acid fortification or supplementation on regulation of these transporters along the intestinal tract is unknown. ObjectiveThe objective was to characterize expression of folate transporters/receptor (FT/R) and folate hydrolase, glutamate carboxypeptidase II (GCPII), from the terminal ileum and throughout the colon of adults and assess the impact of supplemental folic acid. MethodsIn this 16-wk open-labeled randomized clinical trial, adults consumed a low folic acid-containing diet, a folate-free multivitamin, and either a 400 μg folic acid supplement or no folic acid supplement. Dietary intakes and blood were assessed at baseline, 8 wk, and 16 wk (time of colonoscopy). Messenger RNA (mRNA) expression and protein expression of FT/R and GCPII were assessed in the terminal ileum, cecum, and ascending and descending colon. ResultsAmong 24 randomly assigned subjects, no differences in dietary folate intake or blood folate were observed at baseline. Mean ± SD red blood cell folate at 16 wk was 1765 ± 426 and 911 ± 242 nmol/L in the 400 and 0 μg folic acid group, respectively (P < 0.0001). Reduced folate carrier, proton-coupled folate transporter, and folate-receptor alpha expression were detected in the terminal ileum and colon, as were efflux transporters of breast cancer resistance protein and multidrug resistance protein-3. Other than a higher mRNA expression of FR-alpha and GCPII in the 400 μg supplement group in the ascending colon, no treatment differences were observed (P < 0.02). ConclusionsFolate transporters are present throughout the terminal ileum and colon; there is little evidence that a low dose of folic acid supplementation affects colonic absorption.This trial was registered at clinicaltrials.gov as NCT03421483.

Mirvetuximab soravtansine (MIRV) in patients with platinum-resistant ovarian cancer with high folate receptor alpha (FRα) expression: Evaluation of sequence of therapy on anti-tumor activity in the SORAYA study (002)

Mirvetuximab soravtansine (MIRV) in patients with platinum-resistant ovarian cancer with high folate receptor alpha (FRα) expression: Evaluation of sequence of therapy on anti-tumor activity in the SORAYA study (002)

Phase III MIRASOL (GOG 3045/ENGOT-ov55) study: Initial report of mirvetuximab soravtansine vs. investigator's choice of chemotherapy in platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate receptor-alpha expression.

LBA5507 Background: Mirvetuximab soravtansine (MIRV), an antibody drug conjugate targeting FRα, demonstrated clinically meaningful antitumor activity in a single arm trial reported previously (Matulonis, JCO 2023). MIRASOL is a randomized phase 3 trial to confirm the efficacy of MIRV vs standard-of-care chemotherapy in patients (pts) with PROC. Methods: 453 PROC pts with high FRα expression (Roche FOLR1 Assay) with 1-3 priors were randomized 1:1 to MIRV 6 mg/kg, adjusted ideal body weight, Day 1 of a 21-day cycle or IC: paclitaxel, pegylated liposomal doxorubicin, or topotecan. The primary efficacy endpoint was progression-free survival (PFS) by investigator (INV) with key secondary endpoints ORR, overall survival (OS), and patient-reported outcomes in hierarchical order; other endpoints included safety and tolerability. Blinded independent central review (BICR) for PFS and ORR were sensitivity analyses. Results: With a data cutoff of March 6, 2023, 227 pts were randomized to the MIRV arm; 226 to the IC arm. Median follow-up was 13.1 months. Baseline characteristics were well balanced across arms; 14% of pts had one, 39% two, and 47% three prior lines of therapy; 62% received prior bev; and 55% received prior PARPi therapy. The study met its primary and key secondary endpoints with statistically significant results in PFS (INV), ORR (INV), and OS (Table). In the bev-pretreated subset (n=281), PFS HR was 0.64 (0.492, 0.842) and OS HR was 0.74 (0.535, 1.036); in the bev-naïve subset (n=172), PFS HR was 0.66 (0.459, 0.942) and OS HR was 0.51 (0.306, 0.860). The adverse event (AE) profile of MIRV was consistent with prior reports: predominantly low-grade ocular (MIRV vs IC all grade 56% vs 9%; grade 3+ 14% vs 0%) and gastrointestinal events (MIRV vs IC all grade 70% vs 66%; grade 3+ 13% vs 15%). Compared with IC, MIRV was associated with lower rates of grade 3+ treatment-emergent AEs (42% vs 54%), serious AEs (24% vs 33%), and discontinuations due to TEAEs (9% vs 16%). Fourteen percent of pts on the MIRV arm remained on study drug vs 3% on the IC arm. Conclusion: MIRV is the first treatment to demonstrate a PFS and OS benefit in PROC compared to IC. The efficacy data, along with the well-characterized safety profile, position MIRV as a new, standard of care for pts with FRα positive PROC. Clinical trial information: NCT04209855 .[Table: see text]

Correlating expression of NaPi2b and FRa in high grade serous ovarian cancer (HGSOC).

5545 Background: Biomarker driven therapies are increasingly being used for gynecologic cancers, with mirvetuximab soravtansine, a Folate Receptor alpha (FRa) targeting antibody drug conjugate (ADC) being a recent FDA approved agent for patients with FRa positive PROC. Uptifitamab rilsodotin (UpRi) is a late-stage, first in class NaPi2b-targeting ADC with a novel scaffold-linker-payload that enables high drug to antibody ratio and a controlled bystander effect. Approximately 29% of HGSOC patients have FRa positive tumors (Roche VENTANA FOLR1 (FOLR-2.1) RxDx Assay. USPI 2022); ~59% have NaPi2b positive tumors (Okeke et al, USCAP 2022). With the high unmet medical need in PROC and the evolving landscape of available treatments, understanding biomarker expression and correlation between FRa and NaPi2b is critical. Here we evaluate NaPi2b and FRa RNA expression correlation in HGSOC. Methods: Tumor samples (N=84) from the Ph1b UpRi expansion (EXP) cohort were analyzed via Nanostring (770 immune-focus genes from IO 360 panel + 30 customized ADC-related genes) to evaluate the association between NaPi2b and FRa expression. The cutoff for NaPi2b RNA positive or negative was based on approximately 60% of HGSOC patients having NaPi2b positive tumors (top 60% of samples based on expression deemed NaPi2b positive; bottom 40% NaPi2b negative) and FRa RNA cutoff assumed that ~30% of samples were FRa positive. To correlate the NaPi2b expression level between RNA and IHC, the N=84 samples with known expression levels via IHC were analyzed via Nanostring. Results: When evaluating NaPi2b and FRa RNA expression correlation, 21% (N=18) of samples had both NaPi2b positive and FRa positive expression. 38% (N=32) samples were NaPi2b positive and FRa negative. No statistically significant association was observed (Chi-squared test, p=0.129). NaPi2b RNA and IHC expression was evaluated; a statistically significant association was observed (Kappa statistic, p=0.001). Results are in the Table below. Conclusions: Based on this analysis of a limited sample size, there does not appear to be an association between FRa and NaPi2b expression, with the majority of NaPi2b positive samples not being FRa positive. Additionally, general NaPi2b prevalence and the correlation of expression between RNA and IHC suggest that NaPi2b may be a rational biomarker to integrate in RNA tumor panel testing. This research underscores the importance of early, comprehensive testing of all relevant biomarkers to guide therapy selection, and suggests that additional research is needed to evaluate the potential association between FRa and NaPi2b expression via IHC. [Table: see text]

GLORIOSA: A randomized, open-label, phase 3 study of mirvetuximab soravtansine with bevacizumab vs. bevacizumab as maintenance in platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer.

TPS5622 Background: Elevated folate receptor-alpha (FRα) expression is a characteristic of epithelial ovarian cancer (EOC), thereby providing a rational target for antibody drug conjugate (ADC) development in ovarian cancer. Mirvetuximab soravtansine (MIRV) is an ADC comprising a FRα-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent that has received accelerated approval for patients with FRα positive platinum resistant ovarian cancer. MIRV in combination with BEV has demonstrated clinically meaningful activity, along with acceptable tolerability, in patients with FRα expressing ovarian cancer.1 Methods: GLORIOSA is a randomized, open-label, phase 3 study designed to evaluate the efficacy of in combination with bevacizumab compared with bevacizumab alone as maintenance for patients with FRα-positive recurrent platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancers who have not progressed after second line platinum-based chemotherapy plus bevacizumab (which may be given on protocol for patients with high FRα tumor expression). Confirmation of high FRα positivity by immunohistochemistry using the Ventana FOLR1 CDx Assay (high expression; ≥ 75% of viable tumor cells staining at 2+ intensity) and 1 prior line of therapy is required for inclusion. GLORIOSA is designed to randomize 418 patients, 1:1 receiving intravenous MIRV at a dose of 6 mg/kg adjusted ideal body weight plus bevacizumab 15mg/kg every 3 weeks or receiving bevacizumab 15mg/kg every 3 weeks until disease progression or unacceptable toxicity. Radiological assessments will be conducted every 9 weeks (± 2 weeks) for 72 weeks, and subsequently every 18 weeks (± 3 weeks) until progressive disease (PD), death, the start of new anticancer therapy, or withdrawal of consent from the study (whichever occurs first). The primary efficacy endpoint is progression-free survival by investigator and will also be assessed as a sensitivity analysis. The secondary endpoints include objective response rate, quality of life, overall survival, and safety and tolerability. GLORIOSA is a global study that opened for enrollment in December 2022. Reference: 1. Gilbert L, Oaknin A, Matulonis UA, et al. Safety and efficacy of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol. 2023; 170: 241–247 Clinical trial information: NCT05445778 .

Efficacy and Safety of Mirvetuximab Soravtansine in Patients With Platinum-Resistant Ovarian Cancer With High Folate Receptor Alpha Expression: Results From the SORAYA Study

(Abstracted from J Clin Oncol 2023;41(13):2436–2445 Approximately 80% of patients with ovarian cancer experience recurrence after platinum-based chemotherapy, and unfortunately nearly all will eventually develop platinum-resistant ovarian cancer (PROC). Treatment in this setting consists of nonplatinum chemotherapy with or without bevacizumab; however, each successive line of therapy in PROC is associated with progressively lower response rates.

Fallopian tubal histogenesis of ovarian endometriosis-A study of folate receptor-alpha expression.

Ovary is a common organ site involved by endometriosis. We previously found that fallopian tube may contribute to the histogenesis of ovarian endometriosis. The finding was novel and requires further studies. We addressed this issue by examining a differentially expressed gene folate receptor alpha (FOLR1) and its protein (FRA) in this study. A total of 144 tissue samples were studied. These included 32-paired tubal-endometrial-ovarian endometriosis samples (n = 96), 18 samples of ovarian endometriosis without corresponding fallopian tube or endometrium, and 30 ovarian tissue samples with ovarian surface epithelia but without endometriosis. Multiple comparisons among groups of ovarian endometriosis, normal fallopian tube and benign endometrium were performed. FOLR1 was highly expressed in the epithelia of fallopian tube and ovarian endometriosis, with paired endometrial samples showing a significantly lower level of expression. Similar differential studies for FRA protein were performed through Western blot and immunohistochemistry (IHC). The expression of folate receptor alpha at both mRNA and protein levels in the tissues (fallopian tube or ovarian endometriosis vs. the endometrium) were significantly different (p < 0.001). All ovarian surface mesothelial epithelia showed negative expression of FRA by IHC. The results further support that the fallopian tube may contribute to the development of ovarian endometriosis. Understanding the tubal contribution to ovarian endometriosis should ultimately contribute to ongoing investigative efforts aimed at identifying alternative ways to prevent and treat endometriosis. High level of FRA expression in the fallopian tube and endometriosis might be considered as potential tissue sites for targeted therapy.

Society of Gynecologic Oncology Journal Club: Controversial conversations in Gynecologic cancer – The ABCs of ADCs (Antibody drug Conjugates)

The Society of Gynecologic Oncology (SGO) Journal Club is held quarterly to discuss topics related to gynecological malignancies. On November 8, 2022, the SGO Journal Club focused on antibody-drug conjugates (ADCs) in gynecologic malignancies, including the pharmacology, toxicities, and results of recent clinical trials leading to FDA approval of two new therapies for cervical and ovarian cancer. The invited discussants included Drs. Erin Hickey Zacholski, Roisin O’Cearbhaill, and Ursula Matulonis who discussed the pharmacology of ADCs, GOG-3023/ENGOT-cx6 (Coleman et al., 2021 May) and the SORAYA study (Ursula Matulonis, Domenica Lorusso, Ana Oaknin, Sandro Pignata, Hannelore Denys, Nicoletta Colombo, Toon Van Gorp, Jason Konner, Margarita Romeo Marin, Philipp Harter, Conleth Murphy, Jiuzhou Wang, Elizabeth Noble, Brooke Esteves, Michael Method, Robert Coleman, Efficacy and Safety of Mirvetuximab Soravtansine in Patients with Platinum-Resistant Ovarian Cancer with High Folate Receptor Alpha Expression: Results from the SORAYA Study (LBA 4), Gynecologic Oncology, Volume 166, Supplement 1, ,2022).

Pediatric Acute Myeloid Leukemia with Co-Occurring BCR::ABL and CBFA2T3::GLIS2 Dual Fusion with Deep Response to FOLR1-Targeting Antibody Drug Conjugate Stro-002 and Tyrosine Kinase Inhibitor

Introduction: Pediatric acute myeloid leukemia (AML) is characterized by significant cytogenetic and molecular heterogeneity. AML with CBFA2T3::GLIS2 fusion (CBF::GLIS) involving infants and very young children is a rare but uniformly refractory disease with high mortality. Laboratory data demonstrates that this fusion is sufficient for leukemic transformation without recurrent secondary variants. These studies have also linked CBF::GLIS fusion to induction of folate receptor alpha (FOLR1) expression in transformed cells (Meshinchi et al, 2020). Incidence of Ph+ de novo (BCR::ABL minor breakpoint, p190 hybrid) disease ranges from 0.5-3% of all AML cases across the age spectrum (Soupir et al, 2017). We, for the first-time, report dual existence of both fusions in a child with AML and discuss novel interventions including combination of a BCR::ABL tyrosine kinase inhibitor (TKI) and antifolate therapy consisting of methotrexate (MTX) and FLOR1-specific antibody-drug conjugate (ADC) STRO-002 (Sutro Biopharma) based on available data regarding its in-vitro preclinical activity in CBF::GLIS disease (Meshinchi et al, ASH abstract, 2021). Case: A 2-year-old girl of Vietnamese descent received a bone marrow examination for bicytopenia and macrocytosis. Flow cytometry confirmed the poor prognostic RAM immunophenotype AML (CD45 dim, HLA-DR negative, CD38 dim, CD56 bright) and FOLR1 expression. Marrow aspirate smears showed numerous hypercellular spicules and blasts with scant cytoplasm and some blebbing but no granules or Auer rods. Marrow exhibited 100% cellularity. CNS was not involved. Review of diagnostic genomic profile mid induction showed a BCR::ABL minor breakpoint fusion as well as CBF::GLIS fusion. The child began AML induction on COG AAML1831 trial randomized to the experimental arm with CPX-351 and gemtuzumab ozogamicin (GO). Due to lack of response to AML therapy at end of Induction (EOI) I, she was taken off protocol and started on modified ALL regimen for Induction II consisting of cytarabine, low dose weekly methotrexate and bimonthly peg-asparaginase with addition of an oral TKI, dasatinib. EOI II marrow examination showed improvement with reduction in blasts (11%) and detectable BCR::ABL but undetectable CBF::GLIS by Q-RT-PCR. Induction III included low dose weekly methotrexate, cytarabine, GO, and dasatinib. EOI III marrow examination showed complete morphologic remission (CR) with no evidence of minimal residual disease (MRD) or fusion transcripts of either clone. Due to availability of a matched sibling donor, the child underwent hematopoietic stem cell transplantation (HSCT); however, was noted to have 3% blasts on day +83 marrow examination despite previously commencing dasatinib post-transplant prophylaxis. BCR::ABL and CBF::GLIS transcripts were again detectable at low levels. Dasatinib dosage was maximized and weekly MTX and bimonthly peg-asparaginase were reintroduced, but the marrow disease burden increased significantly to 78% blasts positive only for CBF::GLIS fusion. Given availability of FOLR1 directed ADC on single-patient compassionate use basis, patient received single agent STRO-001 on a bi-monthly basis. With rising ANC, evaluation of marrow after 2nd STRO-002 dose remarkably showed CR with MRD negative remission by flow and molecular studies. This time remission was consolidated with monthly STRO-002 and donor lymphocyte infusions (DLI). Currently, patient remains in MRD-negative remission after the 3 of 4 planned STRO-002/DLI maintenance. Patient has maintained a 100% Lansky play score and tolerated the regimen with only prolonged initial cytopenia requiring supportive care as a toxicity. Plan is to continue TKI and monthly STRO-002 as maintenance therapy. Conclusion: Complete genomic sequencing has revolutionized pediatric AML categorization. It is quite conceivable that (BCR::ABL, CBF::GLIS) dual fusion disease will become a more common finding in future. Although CBF::GLIS AML is uniformly refractory to conventional therapy, targeted therapy with FOLR1-directed STRO-002 was highly effective in eliminating CBF::GLIS clone in this patient, and combination with DLI appears to be feasible. Long-term follow-up is required to assess durability of remission. Additional testing of this approach in a larger patient population is needed to determine the role of STRO-002 in this high-risk pediatric AML population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Folate receptor alpha expression is widely observed in uterine and ovarian carcinosarcoma (209)

<b>Objectives:</b> Folate receptor alpha (FRα) expression has been observed in various cancers, including endometrial, ovarian, lung, and triple-negative breast cancers. FRα is an intriguing therapeutic target, and its expression and clinical significance in uterine and ovarian carcinosarcoma remain to be elucidated. <b>Methods:</b> This retrospective study included patients with gynecologic carcinosarcoma who underwent primary surgery at our institution between 1997 and 2019. Immunohistochemical staining of one representative section of the surgical formalin-fixed paraffin-embedded tissue specimens for FRα was performed using an anti-folate-binding protein/FBP antibody (1:200, ab67422; Abcam, Cambridge, UK). The H-score for FR expression was calculated as follows: 3X+2Y+Z, where X, Y, and Z were the proportions of tumor cells showing strong (3+), moderate (2+), and weak (1+) staining intensities, respectively. FRα-positive staining was defined as more than 5% tumor staining of any intensity and FRα-high as an H-score greater than 50. The association between FRα-high expression and clinical-pathologic features or survival was assessed. <b>Results:</b> Overall, 122 patients with uterine carcinosarcoma and seven patients with ovarian carcinosarcoma were included. In uterine carcinosarcoma, the median age was 62 years (range: 34-87). FIGO (2008) stage distribution was 49, 7, 39, and 26 patients in stage I, II, III, and IV, respectively. FRα expression was observed in all patients, and the median H-score was 50 (range: 10-170). FRα-high showed no significant correlation with age, FIGO stage, a predominant histologic subtype of carcinomatous component, or heterologous sarcomatous elements. During follow-up (median: 30.6 months, range: 0.7-216), 57 patients experienced disease recurrence or died, and 29 patients received palliative chemotherapy. FRα-high was not significantly associated with disease-free survival (HR: 1.16, 95% CI: 0.68-1.98, p=0.58) and overall survival (HR: 1.27, 95% CI: 0.74-2.20, p=0.38), respectively. There was no significant difference in the overall response rate to chemotherapy by FRα-high status. In ovarian carcinosarcoma, all tumor specimens showed FRα expression, and the median H-score was 45 (range: 10-70). The median age was 64 years (range: 55-88), and four patients had FIGO (2008) stage III or IV (57%). <b>Conclusions:</b> FRα expression was observed in all patients with uterine and ovarian carcinosarcoma, but the level of expression was lower than those previously reported in endometrial and ovarian cancers. In uterine carcinosarcoma, there was no significant relationship between FRα overexpression and clinical-pathologic features or prognosis. This widespread FRα expression may provide insights into the development of FRα-targeted therapies for gynecologic carcinosarcoma.