Breakthroughs in Targeted Therapy for Low-Grade Serous Ovarian Carcinoma

RR Hem/Onc Updates, Precision Oncology
Ovarian Cancer

Written by: Dr. Charles K Anderson, MD
Sponsored by Verastem

Low-grade serous ovarian carcinoma (LGSOC) is a rare and molecularly distinct ovarian cancer accounting for <10% of new epithelial ovarian cancers.1,2 Recently, significant progress has been made with new therapy options currently in the developmental phase. LGSOC commonly presents at advanced stages, with over 70% of patients experiencing relapse.3  There is an indication of slower tumor progression, leading to an extended overall survival (OS) of around 97 months, in contrast to the 72 months typically seen in high-grade serous ovarian carcinoma (HGSOC) cases.4 LGSOC patients tend to have a longer median progression-free survival (PFS) of 97 months, whereas HGSOC patients usually experience 35 months before progression.4 While LGSOC tends to progress slowly, the relatively young age of patients at diagnosis and their resistance to traditional cytotoxic therapy indicate that the majority will ultimately succumb to the disease.3,5,6 

Primary treatment for newly diagnosed patients typically involves primary debulking surgery (PDS) if feasible. The historical standard-of-care (SOC) treatment options include cytotoxic platinum and taxane based regiments often combined with bevacizumab or primary endocrine targeted therapy (ET) with aromatase inhibitors, selective estrogen receptor modulators (SERMs) or selective estrogen receptor degraders (SERDs). In a study of 58 patients with recurrent LGSOC who were treated with a total of 108 cytotoxic regimens, a response rate of only 3.7% was observed with other combined data showing a response rate of 0-13%.3,5,6,7

Promising advancements in targeted therapies such as MEK inhibitors and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors with concurrent endocrine therapy, have exhibited potential in treating LGSOC with improved response rates. LGSOC tumors frequently exhibit activating mutations in the mitogen-activated protein kinase (MAPK) pathway and lack TP53 mutations.8 Given that over 60% of LGSOC tumors carry RAS/RAF mutations, multiple phase 2/3 trials have explored the clinical effectiveness of mitogen-activated protein kinase kinase (MEK) inhibitors in patients with recurrent or persistent LGSOC. Response rates of 26% and 16% were observed with trametinib and binimetinib, respectively, but with discontinuation rates of 36% and 31% due to toxicity.2,7

It has been realized that focal adhesion kinase (FAK) activation in the development of resistance to MEK inhibitors, the phase II trial RAMP201 assessed the effectiveness of avutometinib, a dual RAF/MEK inhibitor, administered alone and in combination with defactinib, a FAK inhibitor, for the treatment of recurrent LGSOC. This trial also included stratification by KRAS mutation status.3 In May of 2023, at the American Society of Clinical Oncology, the findings from the RAMP201 trial were unveiled, indicating an objective response rate (ORR) of 45% and tumor shrinkage in 86% of assessable patients who received the combination therapy of avutometinib and defactinib. The phase 3 confirmatory trial, RAMP 301, will evaluate the effectiveness of avutometinib and defactinib compared to SOC chemotherapy or hormone therapy options. These trials indicate that MAPK pathway inhibitors hold promise in offering clinical advantages to individuals with LGSOC.

 Avutometinib and Defactinib Mechanism of Action

  • Avutometinib is a first-in-class oral RAF/MEK clamp that potently inhibits MEK while also blocking the compensatory reactivation of MEK by upstream RAF1,4
  • Defactinib is a selective inhibitor of FAK, a key adaptive resistance mechanism to the RAS/MAPK pathway9,10,11
  • Phase 1 FRAME study (NCT03875820) demonstrated activity of avutometinib + defactinib study -led to FDA Breakthrough Therapy Designation and rationale for the phase 2 ENGOT-ov60/GOG-3052/RAMP 201 (NCT04625270) study12,13

Summary: RAMP 201: Registration-Directed Phase 2 Trial of Avutometinib ± Defactinib in Patients with Recurrent LGSOC

  • Patient selection: Recurrent LGSOC, prior platinum chemotherapy, measurable disease (RECIST v1.1), prior MEK inhibitor allowed
  • Primary Endpoint: ORR- In KRAS mt patients and all patients (KRAS mt & wt)
  • A go forward regimen was identified with 3 sub-part study with selection phase, expansion phase, expansion combination phase
  • Eventual combination dosing chosen was: Avutometinib 3.2 mg PO BIW and Defactinib 200 mg PO BID
    • ORR: 31% overall; 44% in KRAS mt and 17% in KRAS wt
    • Median DOR: 31 months overall
    • Median PFS: 12.9 months overall; 22.0 months in KRAS mt and 12.8 months in KRAS wt
  • Safety profile: toxicity was acceptable as most adverse events were grade 1 and 2. Adverse events were managed primarily with dose interruptions and reductions with only a 10% discontinuation rate of for adverse events
  • These data support the potential for avutometinib + defactinib as a new standard of care for recurrent LGSOC, regardless of KRAS status

 In conclusion, I am impressed with the results of RAMP 201 trial showing efficacy and tolerability much higher than historical controls comparing traditional cytotoxic therapy, endocrine therapy combinations and other MEK inhibitors.  I am optimistic and excited to see the results of the ongoing RAMP 301 trial (https://clinicaltrials.gov/study/NCT06072781).

References:

  1. Lito, P., et al. (2014). Cancer Cell, 25(5), 697-710.
  2. Gershenson, D. M., Miller, A., Brady, W. E., Paul, J., Carty, K., Rodgers, W., Millan, D., Coleman, R. L., Moore, K. N., Banerjee, S., Connolly, K., Secord, A. A., O’Malley, D. M., Dorigo, O., Gaillard, S., Gabra, H., Slomovitz, B., Hanjani, P., Farley, J., & Churchman, M. (2022). Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): An international, randomised, open-label, multicentre, phase 2/3 trial. The Lancet, 399(10324), 541–553. https://doi.org/10.1016/S0140-6736(21)02175-9Zwimpfer, T. A., Tal, O., Geissler, F., Coelho, R., Rimmer, N., Jacob, F., & Heinzelmann-Schwarz, V. (2023). Low grade serous ovarian cancer – A rare disease with increasing therapeutic options. Cancer Treatment Reviews, 112, 102497. https://doi.org/10.1016/j.ctrv.2022.102497
  3. Gonzalez-Del Pino, G. L., et al. (2021). Proceedings of the National Academy of Sciences of the United States of America, 118(36), e2107207118.
  4. Gershenson, D. M., Sun, C. C., Bodurka, D., Coleman, R. L., Lu, K. H., Sood, A. K., Deavers, M., Malpica, A. L., & Kavanagh, J. J. (2009). Recurrent low-grade serous ovarian carcinoma is relatively chemoresistant. Gynecologic Oncology, 114(1), 48–52. https://doi.org/10.1016/j.ygyno.2009.03.001
  5. Gockley, A., Melamed, A., Bregar, A. J., Clemmer, J. T., Birrer, M., Schorge, J. O., del Carmen, M. G., & Rauh-Hain, J. A. (2017). Outcomes of women with high-grade and low-grade advanced-stage serous epithelial ovarian cancer. Obstetrics & Gynecology, 129(3), 439–447. https://doi.org/10.1097/AOG.0000000000001867
  6. Monk, B. J., et al. (2020). Journal of Clinical Oncology, 38(32), 3753–3762..
  7. Manning-Geist, B. L., et al. (2024). Clinical Advances in Hematology & Oncology, 22(5), 205–226.
  8. Vang, R., Shih, I. M., & Kurman, R. J. (2009). Ovarian low-grade and high-grade serous carcinoma: pathogenesis, clinicopathologic and molecular biologic features, and diagnostic problems. Advances in Anatomic Pathology, 16(5), 267-282. https://doi.org/10.1097/PAP.0b013e3181b4fffa.
  9. Dawson, J. C., et al. (2021). Nature Reviews Cancer, 21, 313–324
  10. Shinde, R., et al. (2020). Cancer Research, 80(Suppl 16), CT143.
  11. Kang, Y., et al. (2013). Journal of the National Cancer Institute, 105(19), 1485–1495
  12. Banerjee, S., et al. (2021). Annals of Oncology, 32(Suppl 5), S7.
  13. Verastem Oncology. (2021, May 24). Press release: Verastem Oncology receives breakthrough therapy designation for VS-6766 with defactinib in recurrent low-grade serous ovarian cancer. Retrieved September 28, 2023, from https://investor.verastem.com/node/12421/pdf.

 

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