FOLR1 expression

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.

P2, N=140, Recruiting, Sutro Biopharma, Inc. | Not yet recruiting --> Recruiting

P2, N=140, Not yet recruiting, Sutro Biopharma, Inc.

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. 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.

The study is enrolling in Part 1 Q2W Cohort 301 and Q3W Cohort A in the US. Clinical trial information: NCT05001282.

The study is currently enrolling at sites in the US, with future enrollment in China planned (NCT05579366). Clinical trial information: NCT05579366.

The mirvetuximab soravtansine plus bevacizumab doublet is an active and well-tolerated regimen in patients with FRα-expressing platinum-resistant ovarian cancer. Promising activity was observed for patients regardless of level of FRα expression or prior bevacizumab. These data underscore the potential for mirvetuximab soravtansine as the combination partner of choice for bevacizumab in this setting.

The study is actively enrolling in the US and currently recruiting in Q2W Cohort 201 and Q3W Cohort A. QW Cohorts 1-3 and Q2W Cohort 101 are complete. Clinical trial information: NCT05001282.

PK, immunogenicity, and antitumor activity will also be evaluated. The study is currently enrolling at sites in the US, with future enrollment in China planned (NCT05579366).

Furthermore, demonstration of these anti-FRα NPs generating tumor specific contrast in MRI is currently under the way. These studies lay the groundwork for use of bio-safe magnetic particles as a detection and contrast agent for early ovarian cancer detection with improved accuracy to minimize the needs of invasive biopsies/surgery as well as potential utility for monitoring therapy response or recurrence.

These findings demonstrate the feasibility of a preclinical CAR T cell approach targeting FOLR1 as treatment option for ovarian cancer and potentially other FOLR1-expressing tumors.

In summary, PRO1184 is a promising development candidate for the treatment of FRα-expressing solid tumors. A first in human phase 1/2 study in patients with advanced solid tumors is currently recruiting (NCT 05579366).

The compound was also very well tolerated in cynomolgus monkeys with HNSTD at 50 mg/kg and even when administered repeatedly. High conjugation yields along with 100% homogeneity are major drivers of the successful ongoing manufacturing process with planned IND submission in Q4/2023.

Background: MORAb-202 (farletuzumab ecteribulin) is an antibody-drug conjugate (ADC) comprised of the humanized antifolate receptor-alpha (FRα) monoclonal antibody, farletuzumab, and the cytotoxic microtubule inhibitor, eribulin, conjugated by a cathepsin B-cleavable linker. Tumor assessments will be conducted by investigators using RECIST v1.1 at screening, every 6 weeks for 24 weeks, then every 12 weeks or as needed. Assessments of computed tomography scans for ILD will be conducted by a central expert review board.

Furthermore, AZD5335 demonstrated superior activity vs an FRα-MTI benchmark ADC with respect to anti-tumor activity and duration of response in two PDX models with low-to-medium FRα expression at equal or higher drug doses (e.g., in OV0857-CIS: 96% TGI vs 24% TGI at 5 mg/kg and 95% TGI vs 2% TGI at 2.5 mg/kg of a single IV dose AZD5335 and FRα-MTI, respectively). These data indicate that AZD5335 is a promising therapeutic candidate for the treatment of ovarian cancers across the spectrum of FRα-expression.

Increased FRα expression was significantly associated with the presence of fluorescence (p = 0.01), This prospective study sought to determine whether preoperative FRα and FRβ expression on core biopsy IHC correlates with intraoperative fluorescence during pafolacianine-guided surgery. These results, although of small sample size, including limited non-adenocarcinoma cohort, suggest that performing FRα IHC on preoperative core biopsies of adenocarcinomas as compared to squamous cell carcinomas could provide low-cost, clinically useful information for optimal patient selection which should be further explored in advanced clinical trials.

Anti-cancer functions of GM-CSFRα-expressing ICI were suggested. Altogether, the benefits of acquired GM-CSFRα-expressing ICI and GM-CSF for CCA treatment are proposed herein and require elucidation.