Targeting The Folate Receptor in Cancer

Is Folate Receptor alpha the next target for precision medicines in ovarian and other cancer types?

Charles H. Weaver, MD
5–8 minutes
Home » Lung Cancer » Targeting The Folate Receptor in Cancer

Precision cancer medicine is an evolving concept in cancer care that aims to leverage cancer specific genomic information to target treatment of cancer more precisely. Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-growth causing abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision drugs and immunotherapies engineered to directly attack the cancer cells specific abnormalities have an added advantage of leaving normal cells largely unharmed. The rate of overall cancer mortality continues to decline in the United States, and this is largely attributed to breakthroughs with precision cancer medicines and immunotherapy. The first class of precision cancer medicines to approved for ovarian cancer were the PARP inhibitors.

Folates are a family of B vitamins that are active in multiple components of cell metabolism, DNA synthesis, and repair. Folate metabolism has been successfully, albeit broadly targeted in anticancer therapy for almost eight decades and recently entered a new stage, with the approval of the first precision medicine directly targeting the folate receptor–alpha (FR) and cancer cells.1,2 In November 2022, the FDA granted an accelerated approval for the use of Elahere (mirvetuximab soravtansine-gynx) to treat adults with FR positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Cancer cells can use the folate metabolic cycle to fuel their growth, and this has been recognized as one of the hallmarks of cancer. FR alpha is an attractive target for anticancer therapy because research shows it is over expressed on the surface of several kinds of solid cancer cells including non–small cell lung cancer, kidney, and ovarian cancer.2,3 In ovarian cancer, FR alpha is over expressed in 90% of tissue samples. This occurs most commonly with serous subtypes of ovarian cancer but can also occur in clear cell carcinomas.2 FR alpha expression positivity is determined using an immunohistochemistry (IHC) test.4,5

FR alpha expression can also be used to improve surgical outcomes in ovarian cancer. In November 2021, the FDA approved Cytalux (pafolacianine), a fluorescent drug that targets the FR, as an optical imaging agent which can be used for intra-operative identification of ovarian cancer cells.6

About Elahere (mirvetuximab soravtansine)

Elahere is an antibody drug conjugate (ADC) comprised of a humanized FR alpha–directed monoclonal antibody linked to the maytansinoid DM4, an anti-cancer agent targeting tubulin necessary for cancer cell growth. The FDA approved Elahere based on data from the phase 3 SORAYA clinical trial which reported an overall response rate of 32%, including a complete response rate of 5% in patients with advanced platinum resistant ovarian cancer expressing FR alpha.4,7,8

Side effects from Elahere include fatigue, nausea, peripheral neuropathy, and a boxed warning from the FDA about the potential for severe eye side effects, including visual impairment, keratopathy, dry eye, photophobia, eye pain, and uveitis. Overall, 61% of patients treated on SORAYA experienced ocular side effects. The median time to onset was 1.2 months, beginning as late as 13 months from treatment initiation. Half of affected patients had complete resolution of their side effects and 39% had partial improvement. It is recommended that patients undergo an ophthalmic exam including visual acuity and slit lamp exam before starting therapy followed by testing every other cycle for the first 8 cycles and as clinically indicated. Premedication with ophthalmic topical steroids and the use of lubricating eye drops during treatment also are recommended.7,8

About Luvelta STRO-002

Luvelta is a novel antibody drug conjugate (ADC), a type of therapy that combines an antibody that targets a specific protein on the surface of tumor cells with a payload of powerful chemotherapy. Luvelta targets FR alpha with SP8166, which is conjugated to a cleavable DBCO-3-aminophenyl-hemiasterlin drug-linker. The dually conjugated immunostimulant and cytotoxic drug on a single ADC molecule is intended to deliver two different drugs directly to the cancer, and not only kill cancer cells but also locally prime an immune response to the cancer cells.9-12

The phase I dose trial showed that 10 of 31 evaluable patients responded to treatment with a disease control rate of 58% at 16 weeks, and 4 patients were on treatment for 52 weeks, with 3 patients continuing treatment for longer than 64 weeks. To be eligible, patients needed to have recurrent platinum-resistant or -refractory ovarian cancer and have previously received at least 2 platinum regimens and they were enrolled irrespective of their level of FR alpha expression, and no limit was set regarding the number of prior lines of chemotherapy received. The study has expanded and is now enrolling participants from clinical sites throughout the United States and Spain.

About Farletuzumab

Farletuzumab is an investigational humanized ADC that targets FR alpha. Farletuzumab ecteribulin combines farletuzumab and eribulin, a microtubule dynamics inhibitor, using an enzymatically cleavable linker that is also being evaluated in advanced ovarian cancer. Initial reports suggest the combination is effective but is associated with lung toxicity. The overall response rate for patients with high-grade serous, platinum-resistant ovarian cancer was 32% to 50%. Interstitial lung disease/pneumonitis was the most common severe side effect affecting 37 % and 67% of patients in the lower- and higher-dosing cohorts, respectively.13,14

References

  1. Gonen N, Assaraf YG. Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resist Updat. 2012;15(4):183-210. doi:10.1016/j.drup.2012.07.002
  2. Scaranti M, Cojocaru E, Banerjee S, Banerji U. Exploiting the folate receptor αin oncology. Nat Rev Clin Oncol. 2020;17(6):349-359. doi:10.1038/s41571-020-0339-5
  3. Birrer MJ, Betella I, Martin LP, Moore KN. Is targeting the folate receptor in ovarian cancer coming of age? Oncologist. 2019;24(4):425-429. doi:10.1634/theoncologist.2018-0459
  4. Multi-discipline review. Center for Drug Evaluation and Research. December 7, 2022. Accessed December 12, 2022. https://bit.ly/3UOStTZ
  5. Elahere. Prescribing information. ImmunoGen, Inc; 2022. Accessed December 12, 2022. https://bit.ly/3W897z6
  6. List of cleared or approved companion diagnostic devices (in vitro and imaging tools). FDA. Updated December 2, 2022. Accessed December 12, 2022.https://bit.ly/3PiBzMC
  7. Moore KN, Oza AM, Colombo N, et al. Phase III, randomized trial of mirvetuximabsoravtansine versus chemotherapy in patients with platinum-resistant ovarian cancer: primary analysis of FORWARD I. Ann Oncol. 2021;32(6):757-765. doi:10.1016/j.annonce.2021.02.017
  8. A study of mirvetuximabsoravtansine 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 (MIRASOL). ClinicalTrials.gov. Updated October 31, 2022. Accessed December 12, 2022.https://clinicaltrials.gov/ct2/show/NCT04209855
  9. Sutro Biopharma announces STRO-002 FDA fast track designation for patients with advanced ovarian cancer. News release. Sutro Biopharma, Inc. August 18, 2021. Accessed August 18, 2021. https://prn.to/2UuhmLR
  10. Sutro Biopharma announces encouraging interim data on STRO-002 phase 1 dose-escalation study for patients with ovarian cancer. News release. Sutro Biopharma, Inc. December 3, 2020. Accessed August 18, 2021. https://prn.to/3gdpzvD
  11. Naumann RW, Braiteh FS, Diaz JP, et al. Phase 1 dose-escalation study of STRO-002, an anti-folate receptor alpha (FRα) antibody-drug conjugate (ADC), in patients with advanced platinum-resistant/refractory epithelial ovarian cancer. Presented at: 2020 International Gynecologic Cancer Society Virtual Healthcare Conference; September 10-13, 2020; Virtual. https://bit.ly/3iAhP65.
  12. Naumann RW, Uyar D, Moroney JW, et al. STRO-002-GM1, a first in human, phase 1 study of STRO-002, an anti-folate receptor alpha (FRα) antibody drug conjugate (ADC), in patients with advanced platinum-resistant/refractory epithelial ovarian cancer (OC), including fallopian tube or primary peritoneal cancers. Presented at: 2020 AACR Virtual Annual Meeting I; April 27-28, 2020. Abstract CT125.
  13. Armstrong DK, Coleman R, White AJ et al. Efficacy and safety of farletuzumab, a humanized monoclonal antibody to folate receptor alpha, in platinum-sensitive relapsed ovarian cancer subjects: preliminary data from a phase-2 study. Presented at the Joint ECCO 15-34th ESMO Multidisciplinary Congress. Berlin, Germany, September 20-24, 2009. Abstract O-8000.
  14. https://markets.businessinsider.com/news/stocks/eisai-presents-new-findings-for-antibody-drug-conjugate-farletuzumab-ecteribulin-at-2022-asco-annual-meeting-1031509813.
, , , , , ,

You May Be Interested In