Current Standards of Care in Platinum-Resistant Ovarian Cancer
Folate receptor α may be an important treatment target for ovarian tumors.
The standard of care for epithelial ovarian cancer (EOC) and fallopian tube and primary peritoneal cancers at any stage has long been platinum agents. When disease recurs, sensitivity or resistance to platinum agents determines the next choice of therapy.
Based on criteria from the Fourth Ovarian Cancer Consensus Conference, patients are considered platinum refractory if the interval between the last dose of a platinum agent and the date of relapse is less than 1 month, resistant if the relapse is between 1 and 6 months, and sensitive if the platinum-free interval is 6 months or more. Standard guidelines recommend carboplatin or cisplatin doublet therapy with or without bevacizumab (Avastin; Genentech) as first-line agents for a recurrence in platinum-sensitive disease. PARP inhibitors are also recommended for patients that meet certain criteria.1 However, once the cancer becomes resistant or refractory to platinum agents, there are limited, less-effective options available.
Preferred regimens include the sequential use of single-agent nonplatinum cytotoxic therapy, including liposomal doxorubicin, paclitaxel, gemcitabine (Gemzar; Eli Lilly and Company), and intravenous (IV) topotecan (Hycamtin; GlaxoSmithKline). The overall response rates (ORRs) and progression-free survival (PFS) intervals between these agents are similar at 10% to 15%, with PFS between 3 to 4 months and overall survival (OS) approximately 12 months.
Single-agent bevacizumab has an ORR between 16% and 21%.1 Adding bevacizumab to chemotherapy improved PFS to 6.7 months in the AURELIA trial (NCT00976911) but did not change OS.2 Single-agent immunotherapy given without regard to PD-L1 status in EOC has been disappointing, as evidenced by data from the phase 2 KEYNOTE-100 trial (NCT02674061). For pembrolizumab (Keytruda; Merck & Co), the ORR was approximately 9%.3
However, patients with ovarian cancer included in KEYNOTE-158 (NCT02628067) who had DNA mismatch repair–deficient disease or microsatellite instability had a much better ORR of 33%.4 A study that combined all modalities, including oral cyclophosphamide, bevacizumab, and pembrolizumab, reported the ORR at 47.5% in a singlearm phase 2 trial (NCT02853318).5
The PARP inhibitors have improved ORR vs traditional cytotoxic chemotherapy in later lines of therapy, but for this indication, they require BRCA mutation positivity or homologous recombination deficiency, depending on the agent. These genomic mutations or instability are found in a minority of patients.
Currently approved agents in EOC are rucaparib (Rubraca; Clovis Oncology, Inc), niraparib (Zejula; GlaxoSmith-Kline), and Olaparib (Lynparza; AstraZeneca). For rucaparib, the recently reported subgroup analysis in the ARIEL4 trial (NCT02855944) showed an ORR of 47% in the platinum-resistant population.6 In ARIEL4, olaparib has a reported ORR of 31.1%. Further, in the QUADRA trial (NCT02354586), which was evaluating niraparib, investigators reported ORRs of 29% in patients who were platinum resistant and 19% in those who were platinum refractory.7,8
The trials for the later lines of therapy all excluded patients who had received PARP inhibitors in prior lines of therapy. As this class of agents becomes the standard of care in earlier maintenance lines of therapy, further data will be needed to assess whether they retain their activity if patients have already been exposed to PARP inhibitors.
Folate Receptor α
There is still a need to improve the ORR in trials assessing agents for ovarian cancer that give further options to patients without a targetable mutation with currently approved agents. One target for investigation in this area is folate receptor α (FRα), the most widely expressed of several folate receptors. Folate receptors transport folate into cells via a receptor-mediated endocytosis, which then uses the folate in the synthesis of DNA and RNA.
FRα is an exciting tar get, as it is expressed in over 80% of ovarian tumors, and its distribution in normal cells is limited. The luminal cells it is expressed in (eg, choroid plexus, kidney, lung, and placenta) are generally inaccessible to circulation, except for the tubules of the kidney, limiting the off-target effect of IV-administered drugs. As FRα-targeted agents are generally bound to macromolecules that are excluded from glomerular filtration, renal toxicities are expected to be limited, and initial safety data support that.9,10
Initial research targeting FRα looked at small molecule–folate conjugates (vintafolide) and FRα-directed monoclonal antibodies, such as farletuzumab (MORAb-003). Although they had promising phase 2 trials, both approaches failed in phase 3 trials.9 However, antibody-drug conjugates (ADCs) have shown more promise. Currently, mirvetuximab soravtansine (IMGN853), an ADC, is on fast-track approval with the FDA for ovarian cancers after a recent readout of data from the phase 3 SORAYA trial (NCT04296890).
Mirvetuximab soravtansine works by the antibody attaching to FRα. Via endocytosis, the molecule enters the cell and the antibody is cleaved from its ADC maytansinoid DM4 (DM4), which exerts potent antimitotic activity via the inhibition of tubulin, resulting in cell death. One advantage of DM4 is that its active metabolites may also diffuse into neighboring cells and induce further cell death, which is called bystander killing, so cells that do not have the FRα receptor are also vulnerable.11
The SORAYA trial met its primary end point of improved ORR at 32.4% in comparison with the 12% standard of single-agent nonplatinum chemotherapy. The duration of response was 5.9 months, which is an improvement vs the expected 3 to 4 months with chemotherapy. Adverse events (AEs) were similar to those in previous studies of mirvetuximab soravtansine, with no new safety concerns reported.
Treatment-related AEs (TRAEs) led to dose reductions in 19% of patients, dose delays in 32% of patients, and discontinuations in 7% of patients. The most common TRAEs included blurred vision (41% all grades; 6% grade 3+), keratopathy (35% all grades; 9% grade 3+), and nausea (29% all grades; 0% grade 3+).12 If approved, mirvetuximab soravtansine would be the first available agent targeting the FRα receptors.
Patient selection is critical for the FRα-targeted agents. The FORWARD I trial (NCT02631876) of mirvetuximab soravtansine, which included medium (50%-74% of cells) and high expression (> 75%) of FRα on tar geted tumors, failed its primary end point of PFS improvement vs chemotherapy, but, the high-expression subgroup did show improvement. Based on this improvement, the SORAYA trial recruited only high-expression patients, and it is likely that this will be reflected in its indication if the drug is approved.
Because FRα is expressed on other solid tumors, these results could be applicable to other disease states. Farletuzumab, which failed as a monotherapy, has been conjugated with eribulin, and this ADC (MORAb-202; farletuzumab-ecteribulin) reported phase 1 data that include not only ovarian cancer, but also other solid tumors with FRα overexpression, such as triple-negative breast cancer and non–small cell lung cancer.13 The phase 2 trial is ongoing.
ABOUT THE AUTHOR
Tae Smith, PharmD, BCACP, is a clinical pharmacy specialist at the University of Rochester Medical Center in New York.
1. Pujade-Lauraine E, Banerjee S, Pignata S. Management of Platinum-Resistant, Relapsed Epithelial Ovarian Cancer and New Drug Perspectives. J Clin Oncol. 2019;37(27):2437-48. doi:10.1200/JCO.19.00194
2. Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, et al. Bevacizumab Combined With Chemotherapy for Platinum-Resistant Recurrent Ovarian Cancer: The AURELIA Open-Label Randomized Phase III Trial. J Clin Oncol. 2014;32(13):1302-8. doi:10.1200/JCO.2013.51.4489
3. Matulonis UA, Shapira R, Santin A, Lisyanskaya AS, Pignata S, Vergote I, et al. Final results from the KEYNOTE-100 trial of pembrolizumab in patients with advanced recurrent ovarian cancer. J Clin Oncol. 2019;38(15):6005. doi:10.1093/annonc/mdz135
4. Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord J, et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair–Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2020;38(1):1-10. doi:10.1200/JCO.19.02105
5. Zsiros E, Lynam S, Attwood KM, Wang C, Chilakapati S, Gomez EC, et al. Efficacy and Safety of Pembrolizumab in Combination With Bevacizumab and Oral Metronomic Cyclophosphamide in the Treatment of Recurrent Ovarian Cancer: A Phase 2 Nonrandomized Clinical Trial. JAMA Oncol. 2021;7(1):78-85. doi:10.1001/jamaoncol.2020.5945
6. Oza AM, Lisyanskaya AS, Fedenko AA, Dvorkin M, de Melo AC, Shparyk YV, et al. Subgroup analysis of rucaparib versus chemotherapy as treatment for BRCA-mutated, advanced, relapsed ovarian carcinoma: Effect of platinum sensitivity in the randomized, phase 3 study ARIEL4. J Clin Oncol. 2017;39(15):5517. doi:10.1016/S1470-2045(16)30559-9
7. Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, et al. Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation. J Clin Oncol. 2015;33(3):244-50. doi:10.1200/JCO.2014.56.2728
8. Zejula. Package insert. GlaxoSmithKline, Research Triangle Park, NC 27709; May 2021.
9. Birrer MJ, Betella I, Martin LP, Moore KN. Is Targeting the Folate Receptor in Ovarian Cancer Coming of Age? Oncologist. 2019;24(4):425-9. doi:10.1634/theoncologist.2018-0459
10. Elnakat H, Ratnam M. Distribution, functionality and gene regulation of folate receptor isoforms: implications in targeted therapy. Adv Drug Deliv Rev. 2004;56(8):1067-84. doi:10.1016/j.addr.2004.01.001
11. Moore KN, Vergote I, Oaknin A, Colombo N, Banerjee S, Oza A, et al. FORWARD I: a Phase III study of mirvetuximab soravtansine versus chemotherapy in platinum-resistant ovarian cancer. Future Oncology. 2018;14(17):1669-78. doi:10.2217/fon-2017-0646
12. Immunogen Presents Full Results from Positive Pivotal Soraya Trial of Mirvetuximab Soravtansine in Ovarian Cancer at SGO Annual Meeting [Press release]. March 19, 2022. https://investor.immunogen.com/news-releases/news-release-details/immunogen-presents-full-results-positive-pivotal-soraya-trial
13. Shimizu T, Fujiwara Y, Yonemori K, Koyama T, Sato J, Tamura K, et al. First-in-Human Phase 1 Study of MORAb-202, an Antibody–Drug Conjugate Comprising Farletuzumab Linked to Eribulin Mesylate, in Patients with Folate Receptor-α–Positive Advanced Solid Tumors. Clin Cancer Res. 2021;27(14):3905-15. doi:10.1158/1078-0432.CCR-20-4740