Original article by Xiao Yan | CPHI PharmaSources | March 12, 2025, 16:31, Shanghai

On December 04, 2024, breaking news was announced on the official website of the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA): Kechow Pharma's innovative drug Tunlametinib (HL-085) is proposed to be included in the breakthrough therapy designation. This drug, in combination with Vemurafenib, is intended for the treatment of adult patients with metastatic colorectal cancer (mCRC) harboring the BRAF V600E mutation who have previously undergone systemic therapy. This will also be the first MEK inhibitor specifically for adult patients with metastatic colorectal cancer (mCRC) harboring the BRAF V600E mutation, bringing renewed hope to countless patients and their families who are afflicted by colorectal cancer.

Colorectal cancer has long been one of the malignant tumors posing a severe threat to human health. According to statistics, millions of new cases are reported worldwide each year, with the incidence rate showing a steady upward trend. For patients with mCRC, the spread of cancer cells to other parts of the body makes treatment extremely challenging, often resulting in poor prognoses. Patients with BRAF V600E mutations, in particular, exhibit a poor response to conventional chemotherapy regimens, with significantly impacted survival time and quality of life. In this context, the proposed inclusion of Tunlametinib in combination with Vemurafenib as part of breakthrough therapies undoubtedly offers renewed hope for patients.

Insights into the Current Status of Colorectal Cancer

Colorectal cancer, one of the most common malignant tumors of the digestive system, holds a concerning position in the spectrum of diseases in China. According to the latest statistics, China has seen a significant number of new colorectal cancer cases annually. In 2022, there were 517,100 newly diagnosed cases, accounting for 10.7% of all malignant tumor incidences, with an incidence rate of 36.63 per 100,000. Alarmingly, this figure continues to rise over time. The mortality rate of colorectal cancer is equally alarming. In 2022, there were 240,000 deaths attributed to this disease, representing 9.3% of all malignant tumor-related deaths, with a mortality rate of 17.00 per 100,000. Colorectal cancer consistently ranks among the leading causes of malignant tumor-related mortality, posing a severe threat to public health in China.

Within the colorectal cancer population, patients harboring the BRAF V600E mutation face significantly greater treatment challenges. This mutation is present in approximately 8%–12% of all colorectal cancer cases and is associated with more aggressive disease progression and a markedly poor prognosis. Conventional chemotherapy regimens often fail to deliver satisfactory outcomes for patients with BRAF V600E mutations. The low sensitivity of tumor cells to chemotherapeutic agents leads to rapid disease progression following treatment and a considerably shortened survival time. Meanwhile, patients also endure a range of chemotherapy-associated adverse effects, such as nausea, vomiting, hair loss, and immunosuppression, resulting in a sharp decline in quality of life and immense physical and emotional distress.

Tunlametinib: A New Hope in Cancer Therapy

Tunlametinib, a mitogen-activated protein kinase 1 and 2 (MEK1/2) inhibitor, employs a distinct mechanism of action in the fight against cancer. The unchecked proliferation of tumor cells heavily relies on intricate intracellular signaling pathways, among which the RAS-RAF-MEK-ERK pathway plays a pivotal role. When tumor cells have a BRAF V600E mutation, this signaling pathway functions like an "accelerator", becoming persistently activated and continuously transmitting signals that stimulate cell proliferation, leading to uncontrolled division and growth of tumor cells. Tunlametinib has emerged as a precise inhibitor of MEK1/2 kinases. By selectively suppressing their activity, it acts like a robust "roadblock" on the signal transduction pathway, effectively blocking signal transmission, thereby curbing tumor cell proliferation and striking at the root cause of tumor growth. This targeted inhibition of specific signaling pathways not only enhances treatment specificity but also minimizes damage to normal cells and reduces adverse drug reactions, offering patients a more effective and safer therapeutic experience.

At the European Society for Medical Oncology (ESMO) Congress 2023, the Phase I study results of Tunlametinib combined with Vemurafenib in patients with advanced BRAF V600 mutant solid tumors were unveiled. Among the data, findings concerning patients with mCRC were particularly noteworthy. This combination therapy demonstrated promising efficacy among 24 evaluable patients with mCRC who participated in the study. At all dose levels, the objective response rate (ORR) reached 25.0%, indicating that one-quarter of the patients experienced a significant reduction in tumor size. The median duration of response (mDoR) was 5.5 months, enabling patients to maintain tumor remission for an extended period. The median progression-free survival (mPFS) was 6 months, during which time no further disease progression was observed. These results demonstrate clear advantages over traditional treatment approaches, offering new hope for patients with mCRC. Although this is only a Phase I study, the preliminary findings reveal substantial potential for Tunlametinib combined with Vemurafenib in treating mCRC with BRAF V600E mutation, laying a robust foundation for further clinical research and the development of therapeutic regimens.

From a safety perspective, while all patients experienced treatment-related adverse events (TRAEs), the overall safety profile is comparable to that of other combinations of BRAF inhibitors and MEK inhibitors, and is clinically manageable and acceptable. The most frequently observed TRAEs were anemia (61.1%), blood creatine kinase increased (56.9%), and rash (54.2%). Most of these adverse reactions could be mitigated or managed through appropriate clinical interventions. The most common Grade 3–4 TRAEs were anemia (18.1%) and blood creatine kinase increased (13.9%). While 11.1% of patients discontinued the study due to TRAEs, with decreased ejection fraction being the most prevalent reason (2.8%), only 6.9% of deaths were attributed to treatment-emergent adverse events (TEAEs). Most fatalities were linked to underlying conditions, such as two cases of death from compromised baseline cardiopulmonary function, two from disease progression, and one from sudden death. This indicates that with close monitoring and appropriate management, patients are generally able to tolerate the treatment regimen of Tunlametinib combined with Vemurafenib.

In the subsequent Phase II trial, although the enrollment population was further expanded, the observed ORR remained at the level reported in the previous Phase I study, and the PFS exceeded 6 months. For patients with colorectal cancer harboring BRAF V600E mutations, previous chemotherapy-only regimens resulted in a very short survival duration. The combined use of MEK and BRAF inhibitors in this case has achieved disease control lasting over six months, representing a significant therapeutic advancement. According to the latest data from the CDE official website, Tunlametinib has been designated as a breakthrough therapy and is being used in combination with Vemurafenib for the treatment of metastatic colorectal cancer (mCRC) with BRAF V600E mutations in patients previously treated with systemic therapy. It has become the first MEK inhibitor in China to enter Phase III clinical trials for colorectal cancer.

March 2024 marked a significant milestone for Tunlametinib, which received its first approval for marketing from the National Medical Products Administration (NMPA) for the treatment of advanced melanoma with NRAS mutations in patients who have failed anti-PD-1/PD-L1 therapies. This represents a major breakthrough for MEK inhibitors developed in China, offering melanoma patients an innovative treatment option. In the field of melanoma treatment, Tunlametinib has quickly gained prominence due to its unique mechanism of action and robust clinical efficacy. Its approval bridges the gap in targeted therapies for advanced NRAS-mutant melanoma in China, ensuring that patients no longer face challenges due to the lack of effective treatment options.

Subsequently, Tunlametinib was successfully included in the updated 2024 Catalogue of Drugs for Basic National Medical Insurance, with formal implementation set to begin in January 2025. This move undoubtedly brings substantial benefits to patients. The inclusion in medical insurance has significantly enhanced the accessibility of Tunlametinib. Previously, the high cost of new drugs deterred many patients, leaving them no choice but to forgo treatment despite the drugs' remarkable efficacy. The current medical insurance reimbursement policy has alleviated the financial burden on patients, enabling more individuals to access this effective anti-cancer medication. This not only underscores the nation's care and support for cancer patients but also highlights the critical role of the medical insurance system in facilitating the adoption of innovative drugs and enhancing patients' quality of life. From regulatory approval to inclusion in medical insurance coverage, Tunlametinib has swiftly delivered tangible benefits to patients, while establishing a solid foundation for further advancements and applications in colorectal cancer treatment.

Conclusion

In the era of precision medicine, the MEKi combined with BRAFi therapy model, as a representative combination treatment approach, has offered renewed hope for survival and clinical benefits to patients with refractory colorectal cancer. This therapy has paved the way for the development and exploration of inhibitors targeting KRAS mutations, such as G12C and G12D, as well as pan-RAS targets. The mechanisms involving the MAPK signaling pathways, including RAS and RAF, in tumor progression and metastasis are being progressively elucidated through an increasing number of exploratory studies. With the advancing promotion of precision medicine and deeper understanding in this field, the treatment landscape for colorectal cancer is expected to progress toward a path of personalized, precise, and sustainable development.

The proposal to include Tunlametinib in combination with Vemurafenib as a breakthrough therapy marks a significant milestone in the treatment of colorectal cancer. This combination therapy offers unprecedented hope for patients with mCRC harboring the BRAF V600E mutation and holds the potential to redefine the prognosis for this patient population. We hope that the innovative research and development in Chinese companies will capitalize on this breakthrough in the use of MEK inhibitors in colorectal cancer treatment, expedite research efforts, ensure the smooth progress of clinical trials, and establish a robust foundation for the approval of indications for this combination therapy and its timely inclusion in medical insurance, thereby further improving drug accessibility for patients. We firmly believe that in the near future, colorectal cancer patients in China will have access to new treatment options, significantly improving therapeutic benefits for those with refractory colorectal cancer.