To this day, liver cancer is still the top killer on my country's cancer "killer list". According to the latest data on cancer in China in 2022 released by the National Cancer Center (NCC) in February 2024, liver cancer ranked second with 316,500 deaths.

The core reason is that despite the continuous progress in first-line treatment, the existence of drug resistance has made the current second-line treatment of liver cancer face great challenges.

First of all, for patients whose disease progresses after TKIs treatment, the clinical needs are far from being met. Whether it is changing TKIs or using immunotherapy, the degree of clinical benefit needs to be improved.

Specifically, the key trials of multikinase inhibitors regorafenib and cabozantinib in patients whose disease progressed after sorafenib treatment showed that the objective response rate (ORR) was only 11% and 4%, respectively, and the proportion of patients who achieved remission was extremely low.

The role of immunotherapy is also very limited. The ORR of single-drug immunotherapy for this patient group generally does not exceed 20%, and the safety and efficacy of combination therapy are often difficult to balance, which is also unsatisfactory.

Secondly, for patients whose disease progresses after immunotherapy, they face the dilemma of "no drug available".

The core problem is that the current approval of second-line treatment drugs for liver cancer is mostly based on TKIs represented by sorafenib as first-line treatment, and for patients who fail first-line immunotherapy, the existing second-line treatment options are not enough to meet their treatment needs.

However, it is difficult to provide satisfactory data for the exploration of this demand. So far, whether it is TKIs, immunotherapy, or a combination of immunotherapy and TKIs, the research results in the patient group whose disease progresses after immunotherapy can be described as "disaster-level" performance.

For example, a study published at this year's ASCO conference showed that for patients whose disease progressed after receiving the current first-line standard treatment (atezolizumab combined with bevacizumab), the best objective response rate was only 5.9% when the strategy of immune + TKI (regorafenib combined with pembrolizumab) was adopted, and only 4 of 68 patients responded to the regimen.

The powerful combination of nivolumab and ipilimumab does not seem to have much room for development. In some prominent retrospective studies, the objective response rate was only about 20%.

Compared with the former, the challenges faced by the progress of immunotherapy need to be solved more quickly. After all, because of the outstanding efficacy of immunotherapy, its position in the first-line treatment of liver cancer is becoming increasingly solid.

The 2022 edition of my country's "Guidelines for the Diagnosis and Treatment of Primary Liver Cancer" has made immunotherapy the first choice for first-line treatment. According to the data of the "Mijian Liver Cancer Patient Quality of Life Survey 2022", as early as 2022, the proportion of Chinese liver cancer patients receiving immunotherapy has reached 44.7%, and this number will inevitably increase significantly in recent years.

This also means that the problem of immune resistance will appear in more liver cancer patients. Therefore, the current second-line treatment of liver cancer urgently needs a strong "drug", especially for those liver cancer patients who are resistant to immunotherapy, and there needs to be clear evidence to support its efficacy.

Despite the huge challenges, there are many pharmaceutical companies that are brave enough to enter this field from a global perspective, which also means that changes may happen at any time. Based on the exploration of the past few years, targeted drugs developed with precision treatment as the idea have shown great potential.

For example, at the ESMO conference in 2024, Heyu Pharmaceutical announced the latest research results of the FGFR4 inhibitor ipagotinib, which brought new hope for the second-line treatment of liver cancer.

This study is about ipagotinib monotherapy for patients with advanced hepatocellular carcinoma with overexpression of FGF19. Among the patients enrolled, a high proportion of them were in the "poor prognostic characteristics" group.

Specifically, in the 220mg twice daily treatment group, BCLC stage C accounted for 95%, which means that most of them were patients with advanced liver cancer (BCLC stages are divided into 0, A, B, C, and D, with D being the most serious and C being the second).

In this group, the proportion of AFP ≥ 400 (indicating a higher degree of malignancy) reached 82.5%, and 77.5% of patients had extrahepatic metastases.

In addition, 64.9% of patients had received at least two lines of treatment, 85.1% of patients had received ICI treatment, and 75.7% of patients had received ICIs and mTKIs treatment, which means that most of them were patients for whom existing treatments had failed.

However, in a patient group that seemed to be more challenging to treat, ipagotinib showed excellent efficacy: in the ipagotinib 220mg twice daily treatment group, the total ORR reached 36.8%.

Currently, the best performing second-line therapy for patients with disease progression after TKIs is the combination of nivolumab and ipilimumab, with an ORR of only about 32%, and this was achieved when the patient's prognostic characteristics were much better than those of ipagotinib.

In a similar group, the "O+Y" combination for patients after ICI treatment, the ORR that performed better in retrospective studies was only about 20%.

This suggests that ipagotinib has the potential to be a strong support for patients who progress after immunotherapy. Indeed, some responders have shown deep responses.

For example, a 37-year-old male FGF19-positive hepatocellular carcinoma patient was previously treated with sintilimab + bevacizumab. In the third cycle, 89% of the target lesions were observed to shrink rapidly, and the target lesions achieved complete remission in the fifth cycle.

More importantly, ipagotinib is expected to treat patients who have failed both immunotherapy and multi-target inhibitors.

The current drugs for liver cancer are mainly ICI and TKI with anti-angiogenesis as the main mechanism. Once both treatment mechanisms fail, patients have very limited treatment options.

Data published at ESMO 2024 showed that among patients who had received ICI and TKI treatment, the total response rate of 220 mg of ipagotinib twice daily reached 44.8%, mDoR was 7.4 months, and mPFS was 5.5 months.

For patients with worse prognostic characteristics, ipagotinib also showed the characteristics of rapid onset and deep remission, which is not easy. Referring to the key clinical trials of second-line immunotherapy in the past, mPFS usually does not exceed 3 months.

This also shows that ipagotinib has greater potential in this type of patient group whose medical needs have not yet been met.

At the same time, in terms of safety, ipagotinib also shows unique advantages. Its adverse reaction type is different from that of anti-angiogenic drugs and is easier to manage clinically.

Overall, the positive data shown by ipagotinib in multiple dimensions not only provides a new treatment mechanism to fight liver cancer, but also lays a solid foundation for the development of multiple combined treatment options in the future. This also means that it is expected to change the landscape of liver cancer treatment and become a new "game changer".

For pharmaceutical companies, liver cancer treatment drugs are undoubtedly an area worthy of attention.

From a global perspective, the patient population of hepatocellular carcinoma is huge, especially in China. There are about 1 million new cases of liver cancer worldwide each year, of which China accounts for about 50%, and the incidence rate is currently increasing year by year.

This also shows that driven by urgent clinical needs, an effective treatment option has great potential. For this reason, lenvatinib can become a blockbuster drug, and its peak sales in the Chinese market even exceeded 1 billion yuan.

The same logic applies to future "game changers". It seems that ipagotinib also has such potential.

FGF19-positive patients account for about 30% of the total number of patients, and the corresponding potential applicable population of ipagotinib in China is about 150,000, and the market size is huge.

At present, ipagotinib is not only being explored in the second-line treatment, but also the early effect of ipagotinib combined with ICI is very positive:

The 220mg BID combined with atilizumab cohort showed outstanding efficacy in patients with FGF19-overexpressing hepatocellular carcinoma, with an ORR of 50%, which refreshed the record of new drugs under development for previously treated liver cancer. At the same time, it verified the potential synergistic effect of PD-L1 inhibitors and FGFR4 inhibitors in patients with FGF-positive hepatocellular carcinoma, reflecting the potential of ipagotinib to extend to the front line.

If the data remains excellent, ipagotinib may have the potential to become a "blockbuster".

Regardless of the subsequent performance of ipagotinib, it has brought important inspiration to the industry: that is, in the face of new challenges in the treatment of liver cancer, we may need to break the traditional thinking framework and jump out of the scope of traditional ICI and TKI.

We look forward to more breakthrough drugs in the field of liver cancer treatment. For patients, this means that they will have more and more effective treatment options.

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