A new option has emerged for fourth-line metastatic colorectal cancer (CRC) treatment. Previously, there were no more drugs available to use, increasing expectations in clinical practice.

In Korea, the survival-extending effect of Fruzaqla (fruquintinib) is evaluated as a potential solution to the unmet needs of CRC patients. The number of patients with CRC is rapidly increasing, making it the number one cancer in Korea, excluding thyroid cancer.

DailyPharm met with Professor Jin Won Kim of Seoul National University Bundang Hospital's Division of Hematology and Medical Oncology and Professor Dirk Arnold of Asklepios Tumorzentrum Hamburg's Division of Hematology and Oncology to discuss Fruzaqla's potential as a standard of care for fourth-line treatment.

Young patients with colorectal cancer surging...20% still diagnosed at stage 4

Approximately 20% of colorectal cancer patients are first diagnosed at the metastatic Stage 4, and even half of those diagnosed with early localized disease develop distant metastasis during treatment. While the 5-year survival rate drops to about 20% when metastasis occurs, there were virtually no treatment options available after the third line, leading to high unmet needs for patients.

Current standard treatments for metastatic colorectal cancer are mainly concentrated on first- and second-line treatments, primarily consisting of combinations of conventional chemotherapy and targeted therapies. In later lines, such as the third line and beyond, effective drugs are rare, and development is slow.

Professor Arnold said, "In the typically-defined first- and second-line treatments, anti-VEGF or anti-EGFR monoclonal antibodies are used in combination with chemotherapy based on fluoropyrimidine, oxaliplatin, and irinotecan." He added, "In later lines, maintaining quality of life becomes the main goal. Third-line and later treatments require a balanced approach that simultaneously considers both prognosis improvement (life extension) and maintaining quality of life."

According to Professor Kim, chemotherapy is the key treatment for Stage 4 colorectal cancer. If the diseases are concentrated in a localized area, such as a liver-only metastasis, surgery is attempted after chemotherapy to reduce tumor size, or surgery is performed immediately depending on the situation.

Professor Kim said, "The pace of new drug development for colorectal cancer is very slow compared to other cancer types, and options remain limited, with treatments used 10 years ago still holding a major position," and added, "Colorectal cancer patients can survive for a little over two years with basic treatment alone, which makes it difficult to prove a 'definite improvement' over existing therapies, often leading to clinical trial failures."

He pointed out that various pharmaceutical companies were reluctant to develop fourth-line treatments for colorectal cancer because profits are uncertain. As a result, the launch of new drugs has been slow compared to other cancer types, forcing patients to continue treatment with drugs that have been in use for over 10 years.

Professor Kim also said, "The first and second-line treatments are well-covered by insurance in Korea. However, third-line and beyond have limited coverage, which significantly reduces treatment options." He added, "Because of this, treatment options decrease, and drug efficacy tends to diminish as the treatment line advances."

VEGFR-targeting Fruzaqla effective after anti-VEGF treatment

Takeda Pharmaceutical Korea's oral targeted anti-cancer drug, Fruzaqla, is expected to shed light on the fourth-line treatment landscape for metastatic colorectal cancer in Korea.

Fruzaqla is a tyrosine kinase inhibitor (TKI) that selectively inhibits vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, which are essential for tumor angiogenesis. Notably, this drug demonstrated effectiveness even in patients who have become resistant to prior anti-VEGF treatment.

Professor Arnold said, "While bevacizumab (a conventional anti-VEGF antibody treatment) binds to VEGF somewhat non-specifically, Fruzaqla has a very high specificity and binding affinity for all known VEGF receptors. It has been reported to be effective even in patients who have failed prior anti-VEGF treatment."

In other words, this drug maximizes drug exposure while minimizing toxicity by precisely targeting only the VEGF pathway and not attacking unnecessary targets. Professor Arnold explained that in real-world clinical settings, a survival-prolonging effect was confirmed with Fruzaqla administration even in a patient group that had already received various anti-VEGF drugs.

The efficacy and safety of Fruzaqla were proven in the large-scale global Phase 3 FRESCO-2 study. This randomized controlled trial included 691 metastatic colorectal cancer patients who had received treatments such as trifluridine/tipiracil (TAS-102) or regorafenib after failing standard therapy.

Professor Arnold said, "Even in some patients who had received both TAS-102 and regorafenib, Fruzaqla's effect was at a level almost identical to the original study." He added, "This is a very encouraging result that shows Fruzaqla provides patients with a consistent and robust therapeutic effect."

Professor Kim also commented, "Fourth-line treatment refers to treatment administered after all existing treatments have been used. Considering this, Fruzaqla is noteworthy for showing a significant therapeutic effect in a patient group with no other alternatives."

Non-reimbursed status·reimbursement listing present challenges...advantage of oral formulation gains attention

Meanwhile, Fruzaqla as an oral formulation is considered a major advantage in terms of patient convenience.

Professor Kim said, "Most colorectal cancer patients have no difficulty with oral intake, and oral drugs can be more effective and convenient for colorectal cancer patients compared to gastric cancer or other cancer types."

In Korea, Fruzaqla was officially launched in June after receiving approval from the MFDS in March, but it has not yet been approved for insurance reimbursement.

Currently, drugs for third-line and later stages of colorectal cancer are not covered by insurance due to concerns about their cost-effectiveness relative to efficacy, resulting in a high burden on patients.

Professor Kim emphasized, "While there are a few drugs that can be used for third-line and later treatments for colorectal cancer, none of them are covered by insurance," and added, "If a new drug comes out and helps patients, we believe it should definitely be covered by insurance."

However, since the requirement for a health-economic evaluation for reimbursement listing is high, it appears that Fruzaqla will also need to undergo subsequent procedures to be included in the reimbursement list, just like other non-reimbursed drugs.

Finally, the experts shared the opinion that it is most important not to give up on treatment for metastatic colorectal cancer.

Professor Kim said, "Colorectal cancer is not a disease that can be completely resolved at once. Continuously pursuing treatment and using every drug available is key to prolonging a patient's survival," and added, "It is important not to give up even during difficult times in the treatment process and to continue with it."