Professor Hao Chunyi: Bioequivalence ≠ clinical equivalence, and the clinical efficacy of lenvatinib generic drugs must be verified

Liver cancer targeting and immunotherapy drugs are fundamentally subverting the treatment concept and clinical practice of advanced hepatocellular carcinoma (HCC), and 2018 is the origin of this revolution
.

In this year, China's National Medical Products Administration approved the first multi-kinase inhibitor lenvatinib for the first-line treatment
of unresectable hepatocellular carcinoma (HCC) in China.

At that time, the approval of this indication broke the situation that the first-line systemic treatment of unresectable HCC had not been approved for 10 years, so it was epoch-making
.
However, the real significance of lenvatinib for promoting HCC treatment in China has only surfaced four years later
.

With lenvatinib officially entering the national medical insurance reimbursement catalogue in 2021, the clinical accessibility of lenvatinib has been improved, and it has gradually become the "mainstay" of middle and advanced HCC system treatment, and has shown great potential
in randomized controlled studies (RCTs) and real-world studies (RWS).

Not only that, in the era when comprehensive treatment of liver cancer has become the mainstream strategy for middle and advanced liver cancer, the organic combination of lenvatinib or lenvatinib-based systematic treatment regimen with local treatment such as surgery, intervention, and radiotherapy has made a "roar" in the field of unresectable HCC treatment, accelerating the "big shift" of liver cancer treatment and making it possible
to cure the former "king of cancer".

In 2021, a number of lenvatinib generic drugs were approved in China, and in 2022, a number of generic drugs entered the "centralized procurement", so that Chinese liver cancer patients are expected to obtain low-cost lenvatinib treatment, while having more personalized choices and improving the accessibility of tumor drugs
.

Is the generic drug of lenvatinib that has entered domestic clinical application by proving that it has bioequivalence with the original drug clinically equivalent to the original drug? Can generic drugs work with innovators to consolidate the cornerstone position of lenvatinib in the treatment of intermediate and advanced HCC? Can highly malignant unresectable HCC be converted into resectable HCC, giving patients a longer chance of survival?

During the 25th Annual Meeting of the Chinese Society of Clinical Oncology (CSCO), this platform interviewed Professor Hao Chunyi, Director of the Department of Hepatobiliary and Pancreatic Surgery, Peking University Cancer Hospital, while reviewing the process of the original lenvatinib to promote HCC treatment, and discussed the challenges
brought by lenvatinib generic drugs to the rapid development of comprehensive treatment of liver cancer in China.

The efficacy "ceiling" of monotherapy

In 2018, The Lancet published the results of a phase III clinical study (REFLECT study) of lenvatinib head-to-head versus sorafenib in the first-line treatment of unresectable HCC, and the overall survival (OS) of lenvatinib was not inferior to that of sorafenib, but significantly better than sorafenib
in terms of progression-free survival (PFS), time to disease progression (TTP), and objective response rate (ORR).

Moreover, the effectiveness of lenvatinib in Chinese liver cancer patients and hepatitis B virus (HBV)-related liver cancer was significantly better than that of sorafenib, and ORR, PFS, TTP and OS were 2.
6 times, 2.
6 times, 3.
0 times and 1.
5 times that of sorafenib, respectively, suggesting that lenvatinib is more suitable for Chinese liver cancer patients
.

Figure 1 REFLECT research results

"Compared to the ORR of 8.
3% of sorafenib, the ORR of 21.
5% of lenvatinib is a huge leap, and it is also better than the ORR of PD-1 immune checkpoint inhibitor monotherapy for HCC," said Professor Hao Chunyi
.

The results of the LEAP-002 study, which presented the final analysis results at this year's European Medical Oncology (ESMO) Congress, once again verified the efficacy of the original lenvatinib and set a new record
for the efficacy and survival benefit of single-agent first-line treatment of unresectable HCC.
The results of this study showed that the median OS of lenvatinib treatment group reached 19.
0 months, which is the longest median OS for unresectable HCC in single-agent first-line therapy, and 34.
1% of ORR (mRECIST by BICR) also refreshed the efficacy data
of monotherapy.

"The two phase III clinical studies REFLECT and LEAP-002 have brought high-level evidence-based medical evidence for the first-line treatment of unresectable HCC with the original lenvatinib monotherapy, and have brought a credible basis for clinical practice"
.

At present, the PD-L1 immune checkpoint inhibitor atezolizumab and PD-1 immune checkpoint inhibitor Cindilimab are approved in China for the first-line treatment of unresectable advanced HCC
in combination with anti-angiogenic drug bevacizumab based on the results of two phase III studies, IMbrave 150 and ORIENT-32, respectively.
In October this year, based on the positive results of the phase III clinical study HIMALAYA, the first first-line treatment of unresectable HCC with PD-L1 combined with CTLA-4 inhibitors was also approved
in the United States.

Professor Hao Chunyi pointed out that one of the drug principles in clinical practice is that under the premise of clinical equivalence, the problem that can be solved with one drug is not considered with two drugs, because one more drug is bound to increase adverse reactions
.

High ORR, low PD charm

For liver cancer patients who can achieve R0 resection, what makes hepatobiliary surgeons "agitated" is the variety of treatment options and options
based on lenvatinib.

"Because this means that those HCCs that are not resectable from a surgical and/or tumor biology point of view, after drug therapy or drug combination with local therapy, can become potentially resectable HCCs, and surgical resection is still the most likely means of long-term survival for HCC," Professor Hao Chunyi noted High ORR and low disease progression (PD) have led to breakthroughs in the clinical practice of liver cancer translational therapy.
"

According to Professor Hao Chunyi, a higher ORR means stronger anti-tumor activity, which can allow more patients to obtain stage reduction/shrinkage, while a lower PD means a low treatment failure rate, thus avoiding the loss of surgical opportunities for borderline resectable patients
.

"In addition, the original lenvatinib has a fast onset of action and can quickly shrink tumors, which is essential for the treatment of advanced HCC with a high degree of malignancy and rapid progression," said Professor Hao
Chunyi.

Professor Hao Chunyi said that when an unresectable HCC systemic treatment regimen can bring 40% ORR, and a part of the population can achieve complete remission (CR), it is impossible for hepatobiliary surgeons not to be shocked, because this means that the combination of systemic treatment regimen with transarterial chemoembolization (TACE), hepatic arterial perfusion chemotherapy (HAIC), radiotherapy and other local treatment methods may bring higher ORR and lower PD, thereby improving conversion rate and R0 resection
。

In fact, as Professor Hao Chunyi said, based on the systematic treatment plan of the original lenvatinib, HAIC, TACE and other interventional treatments are rapidly being used in the treatment of advanced liver cancer, whether in clinical research, translational research or clinical practice, and the origin of this outbreak is in China
.

Many research results show that the comprehensive treatment with the original lenvatinib as the core can bring higher anti-tumor efficacy, and is expected to play an important role
in the future in the downgrade conversion therapy.

The challenge for generic drugs

The patent of the original lenvatinib in China expired in October 2021, and around that time, 5 generic drugs of lenvatinib have been approved for marketing
in China.
The main feature of generic drugs is that they do not need to carry out systematic and large-scale clinical studies to prove their clinical efficacy, so they can be approved for clinical application
relatively quickly.

The approval of generic drugs by administrative regulatory authorities in different countries and regions is different
.
In China, the most important requirement of regulatory authorities for generic drugs is to prove the bioequivalence
of the original drug.

Therefore, proving clinical efficacy is a hurdle that must be overcome for the widespread use of lenvatinib generics, especially for patients with CNLC stage IIb/IIIa who can obtain surgical resection through conversion therapy
.

Professor Hao Chunyi finally said that Chinese liver cancer treatment doctors are in an era of the best liver cancer treatment, because there are still many unknowns and challenges, such as conversion therapy, there are many problems that must be faced and worth exploring; Therefore, we need to carry out a lot of exploration, including registration studies and real-world studies, but an important premise is that we need reliable, high-quality, and effective and safe drugs
.