FOLR1 expression

Our results highlight a need for standardized protocols for FRα testing to ensure accurate biomarker evaluation across varied clinical settings. The heterogeneity in FRα expression, influenced by tumor histology and anatomical origin, warrant further investigation to optimize therapeutic outcomes.

We identified a gene expression signature correlated to high FRα expression and OC prognosis, which may be used to refine therapeutic strategies targeting FRα in OC. These findings warrant validation in larger cohorts.

P3, N=453, Completed, ImmunoGen, Inc. | Active, not recruiting --> Completed

We also report a parallel expression of Shh and MBP in oligodendroglial cells during early post-natal myelination of the mouse brain. Thus, we identify a crucial Shh signal involved in oligodendroglial cell differentiation and remyelination, with potential interest in the design of better-targeted remyelinating therapeutic strategies.

FRα-targeting ADCs, including MIRV, demonstrated definite efficacy and good safety as novel choices for second-line and beyond treatment of advanced or recurrent ovarian cancer. Patients with high FRα expression showed ORR and PFS benefits similar to those in the overall cohort.

As demonstrated among 682 participants, the safety profile of MIRV is well tolerated and consists primarily of low-grade gastrointestinal, fatigue, headache, peripheral neuropathy, and resolvable ocular adverse events.

Though less than in high-grade disease, a notable portion of low-grade tumors were FOLR1+, suggesting FOLR1 expression in LGSOC could be a viable target for this rare histology, particularly in the recurrent setting.

97.5% had prior taxanes, 81% prior poly (ADP-ribose) polymerase inhibitors (PARPi) [74.7% of whom progressed while on PARPi], 64.6% prior bevacizumab, 98.8% had 2+ prior lines of therapy, and BRCA status was 27.8% positive, 72.2% negative. MIRV demonstrated notable efficacy in this heavily pretreated PSOC population, including among those who may have PARPi resistance. MIRV continues to demonstrate a differentiated safety profile consisting primarily of low-grade neurosensory, GI, and resolvable ocular AEs. These data position MIRV to become a novel treatment option for patients in ≥3L PSOC with FRα positive expression.

Introduction Mirvetuximab soravtansine-gynx (MIRV) is an antibody-drug conjugate that binds to folate receptor alpha and delivers a microtubule inhibitor payload...Median PFS did not significantly differ based on number of prior treatment lines (for 1-3 versus >3 lines, P = 0.3) or prior PARP inhibitor ( P = 0.9) or bevacizumab ( P = 0.4) use...Conclusion/Implications MIRV confers meaningful PFS benefit for a subset of individuals. Biomarkers of response and resistance are urgently needed to optimize patient selection for treatment.

P1, N=86, Active, not recruiting, Shattuck Labs, Inc. | Trial completion date: Apr 2025 --> Nov 2024

Our data highlight the need for caution in antibody selection when developing immunohistochemical-based assays, as some FRα antibodies failed to cleanly and specifically identify FRα expression. We identified two antibodies appropriate for further investigation; however, as developed, both stain more intensely than the FDAapproved test and may, therefore, over-select patients for treatment with FRα-targeted therapies intended for use with the FDA-approved companion diagnostic. From these data, we advise the use of the FDAapproved assay for patient selection.

FOLR1 expression was upregulated by VPA, apicidin, and trichostatin A, but downregulated by MS-275 after 24 h treatment. By contrast, HDAC inhibitors exert different regulatory effects on folate carriers. Moreover, HDAC1/2 inhibition may be a potential mechanism involved in altering FOLR1 and SLC46A1 levels.

Here, we report updated nonanalytical results based on a median follow-up of 16.7 months. 453 PROC pts with high FRα expression (VENTANA FOLR1 [FOLR1-2.1] RxDx Assay) with 1-3 prior therapies were randomized 1:1 to MIRV 6 mg/kg, adjusted ideal body weight, Day 1 of a 21-day cycle or ICC: paclitaxel (PAC), pegylated liposomal doxorubicin (PLD), or topotecan (Topo). With a median follow-up of 16.7 months, MIRV demonstrated improved efficacy vs ICC in pts with PROC. The efficacy data, along with the well-characterized safety profile, supports MIRV as the standard of care for pts with FRα positive PROC. Clinical Trial Information: NCT04209855.

97.5% had prior taxanes, 81% prior poly (ADP-ribose) polymerase inhibitors (PARPi) [74.7% of whom progressed while on PARPi], 64.6% prior bevacizumab, 98.8% had 2+ prior lines of therapy, and BRCA status was 27.8% positive, 72.2% negative. MIRV demonstrated clinically meaningful antitumor activity and favorable tolerability in patients with FRα-high PSOC. The efficacy and safety data support the use of MIRV in PSOC patients with ≥ 2 prior platinum-containing regimens or platinum allergy. Clinical Trial: NCT05041257.

Mirvetuximab soravtansine (MIRV), an FRα-targeting antibody-drug conjugate, is active in high-grade serous epithelial ovarian cancer (HGSOC)... FRα was highest in HGSOC and was associated with advanced stage and BRCA status. Sample age, anatomical site, and PFI did not affect FRα expression, suggesting that any sample is suitable for determining FRα status. Variability was observed in cores from the same specimen, which appeared to be driven by tumour heterogeneity versus biological changes.

However, identified gaps, including limited diversity in patient populations, sparse quality of life data, and the need for long-term safety information, indicate areas for future research. Exploration of additional biomarkers predicting mirvetuximab soravtansine responsiveness is essential for personalized treatment.

P1/2, N=374, Recruiting, ProfoundBio US Co. | N=134 --> 374 | Trial completion date: Sep 2025 --> Apr 2026 | Trial primary completion date: Jan 2025 --> Oct 2025

P2, N=114, Active, not recruiting, ImmunoGen, Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Jun 2024 --> Jun 2025

P2/3, N=600, Recruiting, Sutro Biopharma, Inc. | Phase classification: P2 --> P2/3 | N=140 --> 600

Mesenchymal deletion of Alms1 recapitulates metabolic features of AS, including fatty liver. This confirms a key role for Alms1 in the adipose lineage, where its loss is sufficient to cause systemic metabolic effects and damage to remote organs. Hyperphagia in females may depend on Alms1 deficiency in oligodendrocyte precursor cells rather than neurones. AS should be regarded as a forme fruste of lipodystrophy.

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.

This triplet regimen (MIRV+carboplatin+bevacizumab) was highly active, with a tolerable AE profile in participants with recurrent, platinum-sensitive, FRα-expressing ovarian cancer. Thrombocytopenia was the primary cause of dose modifications. These outcomes compare favorably to historical data reported for platinum-based chemotherapy plus bevacizumab regimens in similar patient populations.

Recently, the FDA approved mirvetuximab soravtansine for platinum-resistant ovarian carcinoma with FOLR1 overexpression, typically high-grade serous carcinoma... To our knowledge, this is the largest study to date of FOLR1 expression in USC. Nearly 1 in 5 USC patients are FOLR1+, independent of HER2 status. Further research testing the efficacy of FOLR1-targeted therapy in USC is needed, as approval could potentially double the proportion of patients with available targeted therapies.

Together, these data showed that the assay is highly reliable, consistently producing evaluable results in the clinical setting. The VENTANA FOLR1 Assay is a robust and reproducible assay for detecting FRα expression and identifying a patient population that derived clinically meaningful benefit from MIRV in the SORAYA study.

MIRV and gemcitabine demonstrate promising activity in platinum resistant EOC at RP2D, but frequent hematologic toxicities.

Finally, we performed additional in vitro assays recapitulating immune suppressive mechanisms present in solid tumors and developed a process for the automated manufacturing of our CAR T cell candidate. These findings demonstrate the feasibility of anti-FOLR1 CAR T cells for ovarian cancer and potentially other FOLR1-expressing tumors.

Folate transporters are present throughout the terminal ileum and colon; there is little evidence that a low dose folic acid supplementation affects colonic absorption.

P3, N=418, Recruiting, ImmunoGen, Inc.

FRα-positive CTC detection by noninvasive liquid biopsy is a useful and effective approach for screening of patients with GC.

By modifying folic acid on the surface of liposomes, tumor cells with high expression of folic acid receptors can be effectively targeted, thereby increasing the enrichment of intracellular drugs and improving efficacy. It can also change the delivery pathway, increase the amount of drug entering resistant tumor cells, and overcome resistance.

All patients received prior bevacizumab; 77% of patients received a prior PARP inhibitor. As of the data cutoff of 25-April-2023, median follow-up was 4.5 months. In all of 35 evaluable patients by investigator per RECIST 1.1, confirmed and unconfirmed ORR was 31.4% (95% CI: 16.85%, 49.29%), and 3-month PFS rate was estimated as 73.5%(95% CI: 55.30%, 85.25%). The most common (≥20%) treatment-related adverse events (all grade and grade 3-4) were Keratopathy (57.1% and 14.3%) , Aspartate aminotransferase increased (45.7% and 0%), White blood cell count decreased (37.1% and 2.9%), Alanine aminotransferase increased (37.1% and 0%), Vision blurred (37.1% and 17.1%), Platelet count decreased (37.1% and 5.7%), Neutrophil count decreased (37.1% and 5.7%), and Xerophthalmia (20.0% and 14.3%).

Introduction: Mirvetuximab soravtansine (MIRV) is an anti-folate receptor alpha (FOLR1)-drug conjugate... 41 cervical squamous cell carcinoma (SCC), 35 endocervical adenocarcinoma, 21 uterine serous carcinoma, 14 uterine carcinosarcoma, and 48 ovarian clear cell carcinoma (OCCC) cases were represented in the TMAs and stained with FOLR1 (see Figure 1). 0% of cervical SCC, 0% of endocervical adenocarcinoma, 14% of uterine serous carcinoma, 0% of uterine carcinosarcoma, and 0% of OCCC cases met current FOLR1 positivity criteria (PS2 ≥ 75%) (see Table 1). Figure 1: Examples of H&E and FOLR1 staining in endocervical adenocarcinoma (A-B), uterine serous carcinoma (C-D), and ovarian clear cell carcinoma (E- F) Table 1: FOLR1 PS2 scores of different tumor types Conclusion/Implications: Variable FOLR1 expression was seen in different gynecologic tumor types.

Antitumor activity has been observed at well tolerated dose levels. Dose escalation continues.

Immunostaining and qPCR of spinal cord samples showed decreased oligodendrocyte proteolipid protein and transcription factor Olig2 expression, but no changes in PDGFRα expression. These results suggest astrocyte LCN2 contributes to early events in EAE and reduces damage to mature oligodendrocytes at later times.

FRα expression was observed in all the UCS and OCS specimens, including HER2-negative UCS patients. This widespread FRα expression suggests that FRα-targeted therapies may hold promise for the treatment for gynecologic carcinosarcoma. However, in uterine carcinosarcoma, no significant relationship was observed between FRα expression and clinicopathological features or prognosis.

Chromatin immunoprecipitation, overexpression of mutant YAP1, and treatment with YAP1-TEAD (TEA domain transcription factors) complex inhibitor verteporfin demonstrated regulation of FOLR1 expression by YAP1 and its partner transcription factor TEAD2. By identifying the influence of YAP1-FOLR1 link in DNA damage, our findings suggest that simultaneous depletion of both could amplify the potency of DNA damaging agents, while concomitantly reducing the release of inflammatory mediators and potentially affecting immune modulation. This study also highlights the novel role of FOLR1 as a probable prognostic marker in gliomas, predicting responsiveness to temozolomide and other DNA damaging agents.

The Q2W regimen had a better hematological safety profile with no related discontinuations. Conclusions Safety and efficacy of ELU001 demonstrated expected, manageable safety profile based on the payload, exatecan, with promising activity in heavily pretreated patients across several cancer indications with low, moderate or high FRα expression.

Intratumoral imaging analysis using tumors on day 21st showed an association between the antitumor effect and intratumoral accumulation of eribulin. Conclusions These results suggest that FZEC may be a promising treatment for FRα-expressing EC of all four molecular subtypes.

Methodology 453 PROC pts with high FRα expression (Roche FOLR1 Assay), 1-3 PLOT were randomized 1:1 to MIRV or IC: paclitaxel, pegylated liposomal doxorubicin, or topotecan. MIRV is the first treatment to demonstrate both an OS and a PFS benefit in a phase III trial in PROC. These efficacy data, along with the well-characterized safety profile, position MIRV as a new standard of care for pts with FRα positive PROC.

The National Comprehensive Cancer Network (NCCN) ovarian cancer 2023 guidelines adopted mirvetuximab as 2A, and mirvetuximab combined with bevacizumab as 2B, recommendations. Mirvetuximab represents the first biomarker-directed therapy with an indication specifically for the treatment of PROC. The efficacy and favorable safety profile support further development of mirvetuximab and mirvetuximab combinations in platinum sensitive and newly diagnosed ovarian cancer.

A number of methods have been developed to target FOLR1 in cancer therapy, including the development of FOLR1-targeted imaging agents for cancer diagnosis and the use of folate conjugates to deliver cytotoxic agents to cancer cells that overexpress FOLR1. Therefore, we focus on the most recent developments in employing FOLR1 for cancer diagnosis and treatment in this review, particularly with regard to cancers that affect women.