ELAHERE becomes the first ADC to extend survival in platinum-resistant ovarian cancer, bringing new hope to patients

[by Yu, Suin] "Conventional single-agent chemotherapy has shown limited success in enhancing survival outcomes for patients with platinum-resistant ovarian cancer. However, treatment with ELAHERE (mirvetuximab soravtansine) offers the potential to prolong progression-free intervals and improve overall survival."

ELAHERE, an antibody-drug conjugate (ADC) developed by the multinational pharmaceutical company AbbVie, is emerging as a promising therapeutic option for patients with platinum-resistant ovarian cancer who no longer respond to standard treatments. Although the drug has not yet been produced for use in Korea, ongoing global clinical trials have raised expectations for its potential efficacy in refractory ovarian cancer. In an interview with <THE BIO>, Professor Lim Myong-cheol of the Center for Uterine Cancer at the National Cancer Center (Department of Obstetrics and Gynecology) discussed the clinical relevance of ELAHERE and the prospective shifts it may bring to the treatment landscape upon its introduction in Korea.

◇Targeting overexpressed FRα to destroy cancer cells – A new hope for early-relapsing patients with limited survival chances

ELAHERE is the first ADC designed to target folate receptor alpha (FRα), a biomarker commonly overexpressed in patients with ovarian cancer. The therapy was approved in the United States in March and in Europe in November of last year for the treatment of platinum-resistant ovarian cancer. In Korea, a marketing approval application was filed earlier this year, and regulatory review is currently underway. Notably, ELAHERE was granted orphan drug designation by the Ministry of Food and Drug Safety (MFDS) in January.

ADCs are a next-generation anticancer modality that minimizes harm to healthy cells by linking a cytotoxic drug (payload or warhead) to an antibody that selectively binds to cancer-specific targets. Owing to this precision, they are often described as ‘cancer-homing missiles.’ ELAHERE consists of an antibody (derivative) engineered to specifically recognize FRα, a protein overexpressed on the surface of ovarian cancer cells, conjugated with the potent cytotoxic drug soravtansine (warhead).

"ELAHERE functions much like a 'guided missile.' Once administered, it travels through the body and selectively binds to cancer cells expressing FRα. Only after entering the cancer cells does, it releases its potent cytotoxic agent, effectively destroying them," Lim explained.

"The greatest advantage of this approach lies in its ability to deliver high concentrations of the therapeutic agent directly to cancer cells while minimizing systemic toxicity. This represents truly encouraging news for patients with platinum-resistant ovarian cancer, a population that has long faced a scarcity of effective treatment options," Lim further expressed.

According to Lim, ovarian cancer is a broad term encompassing all malignant tumors that originate not only in the ovaries but also in the adjacent fallopian tubes and peritoneum. Although ovarian, fallopian tube, and peritoneal cancers are classified separately in the disease classification codes, they are clinically regarded as a single disease group. In Korea, approximately 3,800 new cases of ovarian cancer are diagnosed each year.

Although the exact cause of ovarian cancer remains uncertain, several factors are believed to contribute to its development, including ovulation-related mechanisms, genetic predisposition, personal or family history of ovarian, breast, or colorectal cancer, and environmental influences. Women who experience early menarche and late menopause, as well as those who have never given birth or breastfed, are considered to be at a higher risk of developing the disease.

Because ovarian tumors develop deep within the abdominal cavity, performing a biopsy is often challenging. Therefore, diagnosis and staging are confirmed through pathological examination of the removed tissue following surgical intervention. Postoperatively, patients typically receive platinum-based chemotherapy, most commonly cisplatin or carboplatin, as the first-line treatment. Platinum-resistant ovarian cancer refers to disease that no longer responds to these platinum-containing regiments, with resistance generally defined as tumor recurrence or progression occurring within six months after the completion of the last platinum-based chemotherapy.

"In general, when the cancer recurs after a period of six months (platinum sensitivity), there is a high probability that retreatment with platinum-based drugs will be effective," Lim noted. "However, in cases of 'platinum resistance' (recurrence within six months), the tumor has already developed resistance to platinum compounds, making it difficult to expect any therapeutic benefit even with re-administration of the same drugs."

"Even when recurrence occurs after six months, advanced ovarian cancer has a recurrence rate of 70-80%, and eventually, most cases progress to platinum-resistant disease. Once diagnosed with platinum resistance, patients are left with only non-platinum-based single-agent chemotherapy options," he explained. "When available treatment options become severely limited, the prognosis is inevitably poor, representing one of the most challenging circumstances for patients," he added.

◇ELAHERE demonstrates a 32% reduction in mortality risk and extended survival potential but requires careful management of ocular toxicity side effects

In this context, Lim emphasized that ELAHERE has opened a new therapeutic milestone by demonstrating the potential to prolong survival rates. Reflecting on the presentation of the results of the Phase 3 ‘MIRASOL’ clinical trial results at the 2023 American Society of Clinical Oncology (ASCO) meeting, he recalled, "I vividly remember the atmosphere when the data showing improved overall survival (OS) were unveiled. Compared with conventional chemotherapy, ELAHERE reduced the risk of death by 32% and significantly extended OS. The findings were remarkable, not only for prolonging the time to recurrence but also for improving overall survival rates."

According to the results of the MIRASOL Phase 3 clinical trial, patients treated with ELAHERE exhibited significant improvements in progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) compared with those receiving conventional chemotherapy. The study enrolled a total of 453 patients with FRα-positive tumors (IHC 2+, 3+ ≥75%) who had previously undergone one to three lines of chemotherapy.

The median PFS in the ELAHERE-treated group was 5.59 months, representing a 37% reduction in the risk of tumor progression or death compared to the chemotherapy group (3.98 months). The ORR was also markedly higher with ELAHERE (41.9% vs. 15.9%). Furthermore, the median OS reached 16.85 months in the ELAHERE group versus 13.34 months in the chemotherapy group, corresponding to a 32% reduction in the risk of death, an outcome deemed clinically significant.

"Although the four-month increase in median overall survival (OS) is noteworthy in itself, the continued extension of the survival curve, indicating sustained, long-term benefit, is even more meaningful," Lim emphasized. "For the first time in many years, we are witnessing the emergence of a new therapeutic option in a field where improving survival rates was once thought to be nearly impossible."

However, Lim cautioned that every therapeutic agent presents its own spectrum of adverse effects, underscoring the importance of careful management through treatment. In the case of ELAHERE, the most notable adverse event observed in clinical trials was ocular toxicity, manifested as symptoms such as blurred vision, dry eyes, and keratopathy.

"Effective management of adverse events is essential for all potent anticancer drugs. The key point is that most of these side effects (such as ocular toxicity) tend to be mild or moderate in severity, are reversible, and can be adequately controlled through established management protocols," Lim explained.