Tag: Ovarian Cancer

FDA Approves KEYTRUDA® with Paclitaxel for Platinum-Resistant Epithelial Ovarian, Fallopian tube, or Primary Peritoneal Carcinoma

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SUMMARY: The FDA on February 10, 2026, approved Pembrolizumab (KEYTRUDA®) as well as Pembrolizumab and Berahyaluronidase alfa-pmph (KEYTRUDA QLEX®) in combination with Paclitaxel, with or without Bevacizumab (AVASTIN®), for adult patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma whose tumors express PD-L1 (CPS≥1) as determined by an FDA-authorized test, and who have received one or two prior systemic treatment regimens. The FDA also approved the PD-L1 IHC 22C3 pharmDx as a companion diagnostic device to identify patients with epithelial ovarian, fallopian tube, or primary peritoneal carcinoma whose tumors express PD-L1 (CPS≥1) for treatment with Pembrolizumab.

It is estimated that in the United States, approximately 21,010 women will be diagnosed with ovarian cancer in 2026 and 12,450 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women. It accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. Approximately 85% of all ovarian cancers are epithelial in origin, and approximately 70% of all epithelial ovarian cancers are High-Grade Serous adenocarcinomas. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum-based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5-year Overall Survival rate of about 20-30%.

Platinum-resistant recurrent ovarian cancer therefore remains a significant therapeutic challenge, with historically limited options and modest improvements in survival. Previous studies, such as the Phase III AURELIA trial, established weekly Paclitaxel with Bevacizumab as an effective chemotherapy regimen. The potential for chemotherapy to enhance antitumor immune responses provided the rationale for combining Pembrolizumab, an anti–PD-1 antibody, with Paclitaxel, with or without Bevacizumab, in this patient population.

Trial Design

The ENGOT-ov65/KEYNOTE-B96 trial (NCT05116189) was a multicenter, randomized, double-blind, placebo-controlled Phase III study that enrolled 643 patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Eligible patients had received one to two prior systemic therapies, including at least one platinum-based regimen, and had evidence of disease progression within six months after platinum therapy. Patients with primary platinum-refractory disease were excluded.

Participants were randomized 1:1 to receive Pembrolizumab 400 mg every six weeks or placebo, in combination with weekly Paclitaxel 80 mg/m² on days 1, 8, and 15 of each 3-week cycle, with or without Bevacizumab 10 mg/kg every 2 weeks. Prior use of PARP inhibitors, Bevacizumab, or PD-1/PD-L1 agents was allowed. Patients had an ECOG performance status of 0–1, with a median age of 61–62 years and predominance of high-grade serous histology (86%). Approximately one-third of patients had PD-L1 CPS ≥10.

Efficacy Results

The Primary endpoint was Progression-Free Survival (PFS) per RECIST v1.1, with Overall Survival (OS) as a key Secondary endpoint.

  • First interim analysis (median follow-up 15.6 months):
    • Overall population: median PFS 8.3 months with Pembrolizumab vs 6.4 months with placebo (HR 0.70; P<0.0001).
    • PD-L1 CPS ≥1 population: median PFS 8.3 months vs 7.2 months (HR 0.72; P=0.0014).
  • Second interim analysis (median follow-up 26.6 months):
    • PD-L1 CPS ≥1 population: OS improved to 18.2 months with Pembrolizumab vs 14.0 months with placebo (HR 0.76; P=0.0053).
    • Benefits were observed across subgroups, including older patients, prior PARP inhibitor exposure, and short platinum-free interval.
    • Objective Response Rates were higher with Pembrolizumab (53.0% vs 46.6% in PD-L1 CPS ≥1 patients) with longer Duration of Response.

The PFS and OS improvements were consistent regardless of Bevacizumab use, supporting both doublet and triplet strategies in routine practice.

Safety Profile

Pembrolizumab combined with weekly Paclitaxel, with or without Bevacizumab, demonstrated a manageable safety profile. Adverse events were consistent with known toxicities of checkpoint inhibitors and chemotherapy, including immune-mediated events, infusion reactions, and myelosuppression. No unexpected safety signals were reported, confirming the feasibility of this regimen in a platinum-resistant population.

Clinical Implications

KEYNOTE-B96 demonstrates a clinically meaningful improvement in both Progression-Free and Overall Survival, representing one of the longest reported OS durations in platinum-resistant ovarian cancer. The regimen leverages the immune-modulating effects of weekly Paclitaxel and the potential vascular-normalizing and immunosuppressive effects of Bevacizumab, addressing multiple barriers to effective immune activation.

These results support PD-L1 CPS as a predictive biomarker while emphasizing the importance of integrating immunotherapy with established chemotherapy backbones. The findings provide a foundation for sequencing this strategy alongside emerging therapies, including antibody-drug conjugates and other targeted agents, in this difficult-to-treat population.

Conclusion

KEYNOTE-B96 establishes Pembrolizumab plus weekly Paclitaxel, with or without Bevacizumab, as a viable and effective treatment option for patients with platinum-resistant ovarian cancer, delivering meaningful improvements in survival with a manageable safety profile. This trial highlights the potential of immunotherapy combinations in a disease historically considered immunologically “cold” and provides a new evidence-based option in a setting of high unmet need.

Pembrolizumab vs placebo plus weekly paclitaxel ± bevacizumab in platinum-resistant recurrent ovarian cancer: Results from the randomized double-blind phase 3 ENGOT-ov65/KEYNOTE-B96 study. Colombo N, Zsiros E, Sebastianelli A, et al. Presented at: European Society of Medical Oncology Congress 2025; October 17–20, 2025; Berlin, Germany. Abstract LBA3.

Breakthroughs in Targeted Therapy for Low-Grade Serous Ovarian Carcinoma

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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.

 

Long Term Benefits of RUBRACA® Maintenance in Newly Diagnosed Ovarian Cancer

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SUMMARY: It is estimated that in the United States, approximately 19,680 women will be diagnosed with ovarian cancer in 2024 and 12,740 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women. It accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. Approximately 85% of all ovarian cancers are epithelial in origin, and approximately 70% of all epithelial ovarian cancers are High-Grade Serous adenocarcinomas. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum-based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5-year Overall Survival rate of about 20-30%.

DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The two vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 are tumor suppressor genes, and they recognize and repair double strand DNA breaks via Homologous Recombination (HR) pathway. Homologous Recombination is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity.

Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HR repair pathway. At least 15 genes are involved in the Homologous Recombination Repair (HRR) pathway including BRCA1 and BRCA2 genes. Mutations in BRCA1 and BRCA2 account for about 20-25% of hereditary breast cancers 15% of ovarian cancers, in addition to other cancers such as colon, pancreas and prostate. BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic).

The PARP (Poly ADP Ribose Polymerase) family of enzymes includes PARP1 and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive. PARP inhibitors traps PARP onto DNA at sites of single-strand breaks, thereby preventing their repair and generate double-strand breaks. These breaks cannot be repaired accurately in tumors harboring defects in Homologous Recombination Repair pathway genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death.

RUBRACA® (Rucaparib) is an oral, small molecule PARP inhibitor, developed for treatment of ovarian cancer associated with Homologous Recombination DNA repair deficiency (HRD). With regards to ovarian cancer, RUBRACA® is presently approved by the FDA for the maintenance treatment of patients with a deleterious BRCA mutation (germline and/or somatic)- associated recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy.

ATHENA is an international, multicenter, randomized, double-blind, placebo-controlled, Phase III trial, which evaluated first-line maintenance treatment for patients with newly diagnosed advanced ovarian cancer. ATHENA was designed to evaluate RUBRACA® first-line maintenance treatment in a broad group of patients, including those WITHOUT BRCA1 or BRCA2 (BRCA) mutations or other evidence of Homologous Recombination Deficiency (HRD), or high-risk clinical characteristics such as residual disease. ATHENA study has two separate and fully independently powered comparisons evaluating RUBRACA® monotherapy (ATHENA-MONO) and RUBRACA® plus Nivolumab (ATHENA-COMBO), as maintenance treatment in this patient population.

In the ATHENA-MONO trial, patients with Stage III-IV high-grade ovarian cancer undergoing surgical cytoreduction (R0/complete resection permitted) and responding to 4-8 cycles of first-line platinum-doublet chemotherapy, were randomly assigned 4:1 to receive RUBRACA® 600 mg orally twice daily (N=427) or placebo (N=111). A total of 234 patients had HRD, of whom 185 received RUBRACA® and 49 received placebo. Treatment was continued for 24 months, or until disease progression or unacceptable toxicity. Patients were stratified by HRD test status, residual disease after chemotherapy, and timing of surgery (primary surgery versus interval debulking). The median age was 61 yrs, majority of the patients (78%) did not have a BRCA mutation. Patients were stratified by HRD classification (BRCA wild-type/LOH (Loss of Heterozygosity) high-16% or more, BRCA wild-type/LOH low-less than 16%, and BRCA wild-type/LOH indeterminate). The Primary end point of investigator-assessed Progression Free Survival (PFS) was assessed in a step-down procedure, first in the HRD population (BRCA-mutant or BRCA wild-type/LOH high tumor), and then in the Intent-To-Treat (ITT) population. Secondary end points included Overall Survival (OS), investigator-assessed Objective Response Rate (ORR) in patients with measurable disease at baseline, and Duration of Response (DOR) for patients with investigator-assessed confirmed radiographic Complete Response (CR) or Partial Response (PR).

At a median follow up of 26 months, RUBRACA® maintenance after chemotherapy and surgery significantly improved PFS, compared to placebo maintenance, among all subgroups in the Intent-to Treat population including BRCA-mutant, BRCA wild-type/LOH high, and BRCA wild-type/LOH low (HRD-negative) groups.

The researchers have now provided long term follow-up analysis (median follow-up of 37.0 months). In the Intent-To-Treat (ITT) population, the median Time to First Subsequent Treatment (TFST) was 23.3 months in the RUBRACA® group and 12.1 months in the placebo group (HR=0.52). In the HRD population, the median TFST was 32.7 months in the RUBRACA® group and 15.1 months in the placebo group (HR=0.50).

In the ITT population, the median PFS2 was 36.0 months and 26.8 months in the RUBRACA® and placebo groups respectively (HR=0.84). In the HRD population, the median PFS2 was Not Reached in the RUBRACA® group and was 39.9 months in the placebo group (HR=0.75).

The researchers noted that the clinical benefit of RUBRACA® extended beyond first progression and beyond the 2-year completion of treatment, suggesting that starting RUBRACA® maintenance in the first-line setting benefitted patients through and following their second-line treatment. Overall Survival (OS) data were not mature at the time of this analysis.

It was concluded that first line maintenance therapy with RUBRACA® in addition to providing Progression Free Survival benefit compared to placebo, was found to prolong both Time to First Subsequent Treatment and second Progression Free Survival, with manageable toxicity, in patients with newly diagnosed ovarian cancer, regardless of Homologous Recombination Deficiency (HRD) or BRCA mutation status.

Interim post-progression data and updated survival in patients with newly diagnosed advanced ovarian cancer in ATHENA-MONO. Kristeleit RS, O’Malley DM, Lim, MC, et al. Presented at the 2024 SGO Annual Meeting on Women’s Cancer; San Diego, CA; March 16-18, 2024.

Biomarker Driven ELAHERE® in FR alpha-Positive, Platinum-Resistant Ovarian Cancer

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SUMMARY: It is estimated that in the United States, approximately 19,710 women will be diagnosed with ovarian cancer in 2023, and 13,270 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, and accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. About 85% of all ovarian cancers are epithelial in origin, and 70% of all epithelial ovarian cancers are High-Grade serous adenocarcinomas. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum-based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5-year Overall Survival (OS) rate of about 20-30%. Treatment options for patients with platinum-resistant ovarian cancer are limited, and patients are often treated with single-agent chemotherapy, with an Overall Response Rate (ORR) of between 4% and 13%, short duration of response, and significant toxicities.

Approximately 35-40% of ovarian cancer patients express high levels of Folate Receptor alpha (FR alpha), and this expression correlates with advanced stages of disease and more malignant phenotypes. There is limited expression of Folate Receptor alpha in normal tissues and is limited to the choroid plexus, proximal renal tubules, placenta, and endometrium. Testing for Folate Receptor alpha can be performed on fresh or archived tissue.

ELAHERE® (Mirvetuximab soravtansine-gynx) is a first-in-class Antibody Drug Conjugate (ADC), directed against FR alpha, a cell-surface protein highly expressed in ovarian cancer. It is comprised of a Folate Receptor alpha-binding antibody, cleavable linker, and the maytansinoid payload DM4, which is a potent tubulin inhibitor, disrupting microtubule formation, and thereby designed to kill the targeted cancer cells. Microtubules are major components of the cytoskeleton that give shape and structure to cells. ELAHERE® is the first FDA approved ADC for platinum-resistant disease. In the single-arm SORAYA trial, ELAHERE® demonstrated an ORR of 31.7% and median Duration of Response of 6.9 months, in patients with platinum-resistant ovarian cancer, and prior Bevacizumab exposure. These response rates were consistently seen regardless of the number of prior therapies or the use of a prior PARP inhibitor. As a result, the FDA in November 2022 granted accelerated approval to ELAHERE®.

MIRASOL is a confirmatory randomized Phase III trial, conducted to evaluate the efficacy and safety of ELAHERE® versus Standard-of-Care chemotherapy, in patients with pretreated, platinum-resistant ovarian, peritoneal, or fallopian tube cancer, whose tumors express high levels of FR alpha. In this study, 453 eligible patients (N=453) were randomized 1:1 to receive ELAHERE® 6 mg/kg (based on adjusted ideal body weight) IV infusion once every three weeks, until disease progression or unacceptable toxicity (N=227), or investigators choice of single-agent chemotherapy – Paclitaxel, Pegylated Liposomal Doxorubicin, or Topotecan (N=226)). Both treatment groups were well balanced. Approximately 13% of patients had BRCA mutations, 14% of patients had one prior line of therapy, 39% had two prior lines and 47% had three prior lines of therapy. About 62% received prior Bevacizumab and 55% received prior therapy with PARP inhibitors. The Primary efficacy endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Response Rate (ORR), Overall Survival (OS), and Patient-Reported Outcomes in hierarchical order, as well as Safety and tolerability. The median follow up was 13.1 months.

This study met its Primary and key Secondary endpoints with statistically significant improvement in PFS, ORR and OS. The PFS in the ELAHERE® group was 5.62 months compared to 3.98 months in the chemotherapy group (HR=0.65; P<0.0001). The ORR was also higher in the ELAHERE® group at 42% compared with 16% in the chemotherapy group (P<0.0001). The median Overall Survival rate was 16.46 months among patients who received ELAHERE® compared with 12.75 months among those who received single-agent chemotherapy (HR=0.67; P=0.005). The PFS and OS outcomes favored the ELAHERE® group, irrespective of prior exposure to Bevacizumab. Treatment with ELAHERE® was associated with a lower rate of Grade 3 or more Adverse Events and a lower discontinuation rate (9% compared with 16% for the chemotherapy group). The most common adverse reactions including laboratory abnormalities associated with ELAHERE® were vision impairment, keratopathy, fatigue, nausea, peripheral neuropathy, increase in ALT and AST and cytopenias. Product labeling includes a boxed warning for ocular toxicity. The ocular events were reversible and primarily included low-grade blurred vision and keratopathy, which were managed with protocol-defined dose modifications. Approximately 60% of patients with symptoms had resolution prior to their next cycle of treatment, and less than 1% of patients discontinued therapy due to an ocular event.

It was concluded that treatment with ELAHERE® demonstrated a statistically significant improvement in Progression Free Survival and Overall survival, compared to chemotherapy, in patients with platinum-resistant ovarian cancer and high FR alpha expression, independent of Bevacizumab use, and may be the new standard-of-care for this patient group. ELAHERE® is the first FDA-approved Antibody Drug Conjugate and biomarker directed therapy for ovarian cancer, since the approval of PARP inhibitors.

Mirvetuximab Soravtansine in FRα-Positive, Platinum-Resistant Ovarian Cancer. Moore KN, Angelergues A, Konecny GE, et al. N. Engl J Med 2023;389:2162-2174

Late Breaking Abstract – ASCO 2023: Biomarker-Driven ELAHERE® Improves Survival in Platinum-Resistant Ovarian Cancer

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SUMMARY: It is estimated that in the United States, approximately 19,710 women will be diagnosed with ovarian cancer in 2023, and 13,270 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, and accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. About 85% of all ovarian cancers are epithelial in origin, and 70% of all epithelial ovarian cancers are High-Grade serous adenocarcinomas. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum-based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5-year Overall Survival (OS) rate of about 20-30%. Treatment options for patients with platinum-resistant ovarian cancer are limited, and patients are often treated with single-agent chemotherapy, with an Overall Response Rate (ORR) of between 4% and 13%, short duration of response, and significant toxicities.

Approximately 35-40% of ovarian cancer patients express high levels of Folate Receptor alpha (FR alpha), and this expression correlates with advanced stages of disease and more malignant phenotypes. There is limited expression of Folate Receptor alpha in normal tissues and is limited to the choroid plexus, proximal renal tubules, placenta, and endometrium. Testing for Folate Receptor alpha can be performed on fresh or archived tissue.

ELAHERE® (Mirvetuximab soravtansine-gynx) is a first-in-class Antibody Drug Conjugate (ADC), directed against FR alpha, a cell-surface protein highly expressed in ovarian cancer. It is comprised of a Folate Receptor alpha-binding antibody, cleavable linker, and the maytansinoid payload DM4, which is a potent tubulin inhibitor, disrupting microtubule formation, and thereby designed to kill the targeted cancer cells. Microtubules are major components of the cytoskeleton that give shape and structure to cells. ELAHERE® is the first FDA approved ADC for platinum-resistant disease. In the single-arm SORAYA trial, ELAHERE® demonstrated an ORR of 31.7% and median Duration of Response of 6.9 months, in patients with platinum-resistant ovarian cancer and prior Bevacizumab exposure. These response rates were consistently seen regardless of the number of prior therapies or the use of a prior PARP inhibitor. As a result, the FDA in November 2022 granted accelerated approval to ELAHERE®.

MIRASOL is a confirmatory randomized Phase III trial, conducted to evaluate the efficacy and safety of ELAHERE® versus Standard-of-Care chemotherapy, in patients with pretreated, platinum-resistant ovarian, peritoneal, or fallopian tube cancer, whose tumors express high levels of FR alpha. In this study, 453 eligible patients (N=453) were randomized 1:1 to receive ELAHERE® 6 mg/kg (based on adjusted ideal body weight) IV infusion once every three weeks, until disease progression or unacceptable toxicity (N=227), or investigators choice of single-agent chemotherapy – Paclitaxel, Pegylated Liposomal Doxorubicin, or Topotecan (N=226)). Both treatment groups were well balanced. Approximately 13% of patients had BRCA mutations, 14% of patients had one prior line of therapy, 39% had two prior lines and 47% had three prior lines of therapy. About 62% received prior Bevacizumab and 55% received prior therapy with PARP inhibitors. The Primary efficacy endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Response Rate (ORR), Overall Survival (OS), and Patient-Reported Outcomes in hierarchical order, as well as Safety and tolerability. The median follow up was 13.1 months.

This study met its Primary and key Secondary endpoints with statistically significant improvement in PFS, ORR and OS. The PFS in the ELAHERE® group was 5.62 months compared to 3.98 months in the chemotherapy group (HR=0.65; P<0.0001). The ORR was also higher in the ELAHERE® group at 42% compared with 16% in the chemotherapy group (P<0.0001). The median Overall Survival rate was 16.46 months among patients who received ELAHERE® compared with 12.75 months among those who received single-agent chemotherapy (P=0.0046). The PFS and OS outcomes favored the ELAHERE® group, irrespective of prior exposure to Bevacizumab. Treatment with ELAHERE® was associated with a lower rate of Grade 3 or more Adverse Events and a lower discontinuation rate (9% compared with 16% for the chemotherapy group). The most common adverse reactions including laboratory abnormalities associated with ELAHERE® were vision impairment, keratopathy, fatigue, nausea, peripheral neuropathy, increase in ALT and AST and cytopenias. Product labeling includes a boxed warning for ocular toxicity. The ocular events were reversible and primarily included low-grade blurred vision and keratopathy, which were managed with protocol-defined dose modifications. Approximately 60% of patients with symptoms had resolution prior to their next cycle of treatment, and less than 1% of patients discontinued therapy due to an ocular event.

It was concluded that treatment with ELAHERE® demonstrated a statistically significant improvement in Progression Free Survival and Overall survival, compared to chemotherapy, in patients with platinum-resistant ovarian cancer and high FR alpha expression, independent of Bevacizumab use, and may be the new standard-of-care for this patient group. ELAHERE® is the first FDA-approved Antibody Drug Conjugate and biomarker directed therapy for ovarian cancer, since the approval of PARP inhibitors.

Phase III MIRASOL (GOG 3045/ENGOT-ov55) study: Initial report of mirvetuximab soravtansine 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. Moore KN, Angelergues A, Konecny GE, et al. J Clin Oncol 41, 2023 (suppl 17; abstr LBA5507)

Folate Receptor Alpha

RR

Approximately 35-40% of ovarian cancer patients express high levels of Folate Receptor alpha, and this expression correlates with advanced stages of disease and more malignant phenotypes. There is limited expression of Folate Receptor alpha in normal tissues and is limited to the choroid plexus, proximal renal tubules, placenta, and endometrium. Testing for Folate Receptor alpha can be performed on fresh or archived tissue and is considered positive if at least 75% of cells had 2+ staining intensity or greater, based on immunohistochemistry-based scoring. .

ELAHERE® (Mirvetuximab soravtansine-gynx)

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The FDA on November 14, 2022, granted accelerated approval to ELAHERE® (Mirvetuximab soravtansine-gynx) 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® is a Folate Receptor alpha directed antibody and microtubule inhibitor conjugate. Patients are selected for therapy based on an FDA-approved test. ELAHERE® is a product of ImmunoGen, Inc.

FDA Approves Biomarker-Driven ELAHERE® for Platinum-Resistant Ovarian Cancer

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SUMMARY: The FDA on November 14, 2022, granted accelerated approval to ELAHERE® (mirvetuximab soravtansine-gynx) for adult patients with Folate Receptor alpha (FR alpha) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens. The FDA also on the same day approved the VENTANA FOLR1 (FOLR-2.1) RxDx Assay (Ventana Medical Systems, Inc.), as a companion diagnostic device to select patients for the above indication.

It is estimated that in the United States, approximately 19,880 women will be diagnosed with ovarian cancer in 2022, and 12,810 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, and accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. Approximately 85% of all ovarian cancers are epithelial in origin, and approximately 70% of all epithelial ovarian cancers are High-Grade Serous adenocarcinomas. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum-based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5-year Overall Survival rate of about 20-30%. Treatment options for patients with platinum-resistant ovarian cancer are limited, and patients are often treated with single-agent chemotherapy, with an Overall Response Rate of between 4% and 13%, short duration of response, and significant toxicities.

Approximately 35-40% of ovarian cancer patients express high levels of Folate Receptor alpha, and this expression correlates with advanced stages of disease and more malignant phenotypes. There is limited expression of Folate Receptor alpha in normal tissues and is limited to the choroid plexus, proximal renal tubules, placenta, and endometrium. Testing for Folate Receptor alpha can be performed on fresh or archived tissue.

ELAHERE® (mirvetuximab soravtansine-gynx) is a first-in-class Antibody Drug Conjugate (ADC), directed against FR alpha, a cell-surface protein highly expressed in ovarian cancer. It is comprised of a Folate Receptor alpha-binding antibody, cleavable linker, and the maytansinoid payload DM4, which is a potent tubulin inhibitor, disrupting microtubule formation, and thereby designed to kill the targeted cancer cells. Microtubules are major components of the cytoskeleton that give shape and structure to cells. ELAHERE® is the first FDA approved ADC for platinum-resistant disease.

The FDA approval was based on the pivotal SORAYA trial, which is a single-arm study in 106 patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, whose tumors expressed high levels of Folate Receptor alpha, and who had been treated with 1-3 prior lines of systemic treatment regimens. All patients were required to have received prior treatment with AVASTIN® (Bevacizumab). Enrolled patient’s tumors were positive for FR alpha expression as determined by the above-mentioned FDA approved assay. Patients were eligible for the study if at least 75% of cells had 2+ staining intensity or greater, based on immunohistochemistry-based scoring. Patients were excluded if they had corneal disorders, ocular conditions requiring ongoing treatment, more than Grade 1 peripheral neuropathy, or noninfectious interstitial lung disease. Patients received ELAHERE® 6 mg/kg (based on adjusted ideal body weight) IV infusion every three weeks, until disease progression or unacceptable toxicity. Assessments were made for tumor response every six weeks for the first 36 weeks, and every 12 weeks thereafter. The Primary endpoint was investigator-assessed Overall Response Rate (ORR), and key Secondary endpoint was Duration of Response (DOR).

The confirmed ORR was 31.7% including five Complete Responses, and the median Duration of Response was 6.9 months. Response rates were consistently seen regardless of the number of prior therapies or the use of a prior PARP inhibitor. The most common adverse reactions including laboratory abnormalities, were vision impairment, keratopathy, fatigue, nausea, peripheral neuropathy, increase in ALT and AST and cytopenias. Product labeling includes a boxed warning for ocular toxicity. The authors reported that the ocular events were reversible and primarily included low-grade blurred vision and keratopathy, which were managed with protocol-defined dose modifications. Approximately 60% of patients with symptoms had resolution prior to their next cycle of treatment, and less than 1% of patients discontinued therapy due to an ocular event.

It was concluded that ELAHERE® had impressive anti-tumor activity, durability of response, and overall tolerability, and may be a new therapeutic option for patients with Folate Receptor alpha-positive platinum-resistant ovarian cancer.

Efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: Results from the SORAYA study. Matulonis UA, Lorusso D, Oaknin A, et al: 2022 SGO Annual Meeting on Women’s Cancer. Abstract 242. Presented March 19, 2022.