FRα Targeting ADCs for Ovarian cancer

Ovarian cancer has the worst prognosis among the three major gynecologic malignancies, with insidious symptoms and metastasis present in 54.3% of patients at the time of disease onset. The 5-year survival rate of ovarian cancer patients is about 49.7%, while the 5-year survival rate of metastatic ovarian cancer is only 30.8%. The initial treatment of ovarian cancer is based on surgery combined with platinum-based chemotherapy. The overall recurrence rate after initial treatment for epithelial ovarian cancer is 62%, and the recurrence rate for stage III/IV ovarian cancer is 80%-85%. The short survival of patients with platinum-resistant recurrent ovarian cancer is an urgent clinical bottleneck to be addressed.

Antibody-drug conjugates (ADCs) are an emerging class of drugs for the treatment of ovarian cancer. ADC comprises a mAb conjugated to the cytotoxic payload via a chemical linker that is directed toward a target antigen expressed on the cancer cell surface, reducing systemic exposure and therefore toxicity. Such optimized targeted drug delivery can expand the therapeutic index compared with conventional chemotherapeutic drugs. In addition, the structure of ADCs (comprising antibody, linker and drug moieties) provides researchers with opportunities for innovation, so that each component can be optimized to improve efficacy while reducing toxic effects.

Approved FRα ADC for Ovarian Cancer

On November 14, 2022, the Food and Drug Administration (FDA) granted accelerated approval to mirvetuximab soravtansine-gynx (Elahere, ImmunoGen, Inc.), a first-in-class antibody-drug conjugate (ADC) comprising a folate receptor alpha-binding antibody, cleavable linker, and the maytansinoid payload DM4, for adult patients with folate receptor alpha (FRα) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens.

/Elahere-milestones

Figure 1. Pivotal milestone for Mirvetuximab Soravtansine in FRα-positive, platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal cancer who have received 1 to 3 prior systemic regimens. Source: reference 1

This approval was based on the data from the pivotal SORAYA trial, a single-arm trial of 106 patients with FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. Results showed an overall response rate of 31.7%, including five complete responses, for patients who received mirvetuximab soravtansine. Also, the median DOR was 6.9 months.

On May 3rd, 2023, ImmunoGen announced that Elahere met its endpoints in the Phase III confirmatory MIRASOL trial for platinum-resistant ovarian cancer. The MIRASOL trial enrolled a total of 453 patients and the results showed that the median overall survival (mOS) was prolonged from 12.75 months to 16.46 months and the risk of death was reduced by 33% in the Elahere arm compared to the IC chemotherapy arm (carboplatin + irinotecan). Median progression-free survival (mPFS) was extended from 3.98 months to 5.62 months, with a 35% reduction in the risk of disease progression or death. The investigator-assessed objective response rate (ORR) in the Elahere arm was 42.3%, including 12 complete responses (CRs), compared with 15.9% in the IC chemotherapy arm, with no CRs. In terms of safety, compared with IC chemotherapy, Elahere had a lower incidence of adverse events, and no new adverse safety signals were found.

ImmunoGen said that with the success of the MIRASOL trial, Elahere has the potential to become the new standard of care for FRα-positive ovarian cancer.

Introduction of FRα

Folate receptor-α (FRα) is a folate-binding protein (glycosylphosphatidylinositol (GPI)-anchored cell surface protein) encoded by FOLR1 and located on the cell membrane with a molecular weight of approximately 38-40 KD. FRα was originally discovered as a folate-binding protein and was later found to be involved in the regulation of tumor cell proliferation and metastasis in addition to folate transport.

In normal tissues, FRα is hardly expressed. However, in tumor tissues, FRα is widely highly expressed, especially in non-small cell lung cancer (14-74%), triple-negative breast cancer (35-68%), mesothelioma (72-100%), epithelial ovarian cancer (76-89%) and other tumors. Therefore, FRα becomes an ideal target for the development of tumor-targeting drugs.

FRα-target

Figure 2. Cancers overexpressing folate receptor α (FRα) and concordant expression of FRα in non-malignant tissues. Source: reference 4

It was found that FRα is involved in tumor regulation mainly through the following mechanisms. On the one hand, FRα, when combined with folic acid, initiates intracellular regulatory signaling network to regulate the phosphorylation of non-receptor tyrosine kinase PEAK1 to promote the activation of ERK and STAT3, which in turn regulates the proliferation and growth of tumor cells. On the other hand, FRα enables tumor cells to metastasize by downregulating the intercellular adhesion molecule E-calcoplasmin. Therefore, theoretically, by inhibiting FRα, tumor metastasis and invasion can be controlled. However, the development of drugs targeting FRα has gone through a rocky road.

FRα ADCs in Clinical Trials

Currently, there are only a few FRα ADCs in the clinical stage.

1. Sutro Biopharma: STRO-002

STRO-002 is a third-generation ADC developed by Sutro, Inc. It was generated using cell-free antibody production and site-specific conjugation technology. STRO-002 includes the tubulin-targeting 3-aminophenyl hemiasterlin warhead SC209, a novel microtubule inhibitor, joined to the antibody via protease-cleavable linker Val-Cit-PABA.

STRO-002

Figure 3. Cell free technology to enable the Sutro designed ADC. Source: https://www.sutrobio.com/

In phase I clinical trial, data showed an ORR of 31.7% and an mPFS of 4.3 months in 41 patients with platinum-resistant or recurrent ovarian cancer who had received at least 2 lines of therapy. Among the FRα TPS >25%, the ORR was 37.5% and mPFS was 6.1 months in 32 evaluable subjects. In terms of safety, the most common grade 3-4 AEs included neutropenia and arthralgia.

2. Eisai: MORAb-202

MORAb-202 is an FRα targeting ADC consisting of farletuzumab (an antibody that binds to FRα) paired with eribulin mesylate (a microtubule dynamics inhibitor) conjugated via a cathepsin-B–cleavable linker.

At the 2022 ASCO Annual Meeting, Eisai presented data from Study 101, a clinical study of MORAb-202 with platinum-resistant ovarian cancer (PROC), in which 24 patients in cohort 1 received a 0.9 mg/kg dose of the drug with an ORR of 31.6%, and 21 patients in cohort 2 received 1.2 mg/kg of the drug with an ORR of 50.0%. In terms of safety, the most common TEAE was interstitial lung disease (ILD), most of which was low grade.

3. Bio-Thera: BAT8006

In March 2022, the CDE official website showed that the clinical trial application of BAT8006 from Bio-Thera was approved for the treatment of patients with advanced solid tumors.

BAT8006 is composed of recombinant humanized anti-FRα antibody and toxin small molecule topoisomerase I inhibitor, linked by an independently developed cleavable linker. The toxin small molecule has a strong cell membrane permeability with a bystander effect, which can effectively overcome the heterogeneity of tumor cells. Meanwhile, BAT8006 has excellent stability and safety profile, and the toxin small molecules released in plasma are extremely low, reducing the risk of off-target toxicity. Preliminary data showed that 4 of 6 ovarian cancer patients were in partial response (PR) and 2 had stable disease (SD).

Conclusion

In general, the development of the FRα target is difficult, and there are fewer companies developing this target worldwide, but this does not mean that the competition for the FRα target is not fierce. It will be a challenge for the latecomers to stand out, both to achieve outstanding drug efficacy and to control adverse effects. However, high risk often means high reward. FRα, as an ADC target with less competition but clear drug potential, can avoid homogeneous competition and form differentiated advantages.

References:
1. Heo, YA. Mirvetuximab Soravtansine: First Approval. Drugs 83, 265–273 (2023). https://doi.org/10.1007/s40265-023-01834-3
2. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-elahere-mirvetuximab-soravtansine-gynx-fra-positive-platinum#:~:text=On%20November%2014%2C%202022%2C%20the,three%20prior%20systemic%20treatment%20regimens.
3. https://investor.immunogen.com/news-releases/news-release-details/elaherer-demonstrates-overall-survival-benefit-phase-3-mirasol
4. Ruf K, Hasler-Strub U. Folate Receptor α - A New Target for an Old Enemy. healthbook TIMES Oncology Hematology. 2020;5(3):38-43. doi:10.36000/hbT.OH.2020.05.022
5. Li X, Zhou S, Abrahams CL, Krimm S, Smith J, Bajjuri K, et al. Discovery of STRO-002, a Novel Homogeneous ADC Targeting Folate Receptor Alpha, for the Treatment of Ovarian and Endometrial Cancers. Mol Cancer Ther 2023; 22(2):155-167.
6. Safety and efficacy of MORAb-202 in patients (pts) with platinum-resistant ovarian cancer (PROC): Results from the expansion part of a phase 1 trial. Shin Nishio, Mayu Yunokawa, Koji Matsumoto, Kazuhiro Takehara, Kosei Hasegawa, Yasuyuki Hirashima, Hidenori Kato, Hiroki Ikezawa, Maiko Nomoto, Seiichi Hayato, Yohei Otake, Takuma Miura, and Kan Yonemori Journal of Clinical Oncology 2022 40:16_suppl, 5513-5513