Are the Fourth Generation EGFR Inhibitors the Next Wealth Creation Myth?

Recently, WJ13404 Tablet, a first-in-class of Suzhou Junjing Biosciences, has been submitted for clinical application (acceptance No.: CXHL2200202/3). WJ13404 Tablet is a fourth generation of EGFR-TKI (EGFR inhibitor). In September 2020, Junshi Biosciences and Wigen Biomedicine announced an agreement to jointly develop, manufacture and commercialize the fourth generation of EGFR-TKIs globally.

As the "golden" mutation in lung cancer, EGFR is considered as one of the fastest growing and most drug-rich mutations among the targeted drugs, and there are currently three generations of EGFR-TKIs on the market. As the main treatment product for lung cancer patients with EGFR mutations, EGFR-TKIs is promising in market. So what is the market outlook for the fourth generation EGFR-TKIs?

EGFR Inhibitors - God's Gift to the East

Epidermal Growth Factor Receptor (EGFR), a transmembrane tyrosine kinase receptor, plays an important role in the growth, apoptosis, metastasis and proliferation of cancer cells. Specifically, when EGFR is normally expressed, it can be involved in cell growth and division. It is considered as a regulatory switch for human epidermal cells. When EGFR mutates, it overexpresses the tyrosine kinase receptor, which in turn binds to an excess of epidermal growth factor, leading to tyrosine kinase overactivation and uncontrolled cell growth and division.

EGFR inhibitors inhibit the activation of tyrosine kinases by competing with endogenous ligands to bind EGFR and block the EGFR signaling pathway, thereby producing a range of biological effects such as inhibiting the proliferation and metastasis of tumor cells and promoting the development of apoptosis in tumor cells.

It is worth noting that EGFR mutations account for less than 10% of patients with NSCLC in Europe and America, but more than 30% of patients in Asia. Mutations that are rare in European and American patients are significant for Asian patients. It is for this reason that EGFR-TKIs have been called God's gift to the East.

Iteratively Upgraded EGFR-TKIs

The advent of EGFR-TKIs is arguably a landmark event in lung cancer treatment. First-line therapy with EGFR-TKIs can prolong progression-free survival (PFS), improve quality of life and reduce the incidence of serious side effects in patients with EGFR mutations compared to those receiving standard chemotherapy.

However, drug resistance is a constant topic. EGFR-TKIs have been iteratively updated from "birth" to the present in response to the development of resistance in patients' treatment. Currently, the first, second and third generations of EGFR-TKIs are on the market and a number of companies are creating the fourth generation of EGFR-TKIs.

The first generation of EGFR-TKIs are reversible targeted drugs that inhibit the activation of EGFR kinase by competing with ATP for binding to its structural domain. The first generation of EGFR-TKIs are represented by Gefitinib, Erlotinib and Icotinib. However, despite its efficacy, most patients develop resistance to the drugs after 1-2 years of use.

The second generation of EGFR-TKIs are irreversible targeted drugs, represented by Afatinib and Dacomitinib. Due to their use of covalent bonds to irreversibly bind the EGFR kinase active center site, their clinical efficacy has improved compared to the first generation EGFR-TKIs and they are able to overcome the problem of drug resistance to a certain extent. However, the second generation of EGFR-TKIs have not shown better overall survival rates for patients in clinical trials and they can also cause serious side effects such as diarrhea and skin rash.

The third generation of EGFR-TKIs are also irreversible targeted drugs, represented by Osimertinib, which efficiently inhibits EGFR-sensitive mutations and EGFR T790M-resistant mutations, while also showing good efficacy against brain metastases. Osimertinib even set the longest median Progression-Free Survival (mPFS) and median Overall Survival (mOS) in the history of EGFR-TKIs, reaching 18.9 months and 38.6 months respectively, undoubtedly a new peak in treatment history.

As one of the most prevalent cancers in the world, lung cancer has a large patient population, both abroad and at home, so its market outlook is naturally not bad. The sales volume of Gefitinib reached US$67 million in 2002, the first year of marketing; With FDA approval for marketing in 2003, Gefitinib saw the increasing size of the patient population, with the sales volume of US$228 million. As a latecomer, the Erlotinib from Roche, which was approved by the FDA in 2004, has also experienced a surge in sales volume, reaching a peak of US$1.458 billion in 2013. Osimertinib is even a heavyweight with US$4 billion in sales volume in 2020.

This is also the case in China. By modifying the structural formula of the Gefitinib molecule, Betta Pharmaceuticals developed Icotinib, which has seen a rise in sales volume since it began sales in China in 2011: from 2011-2015, the sales volume of Icotinib was RMB 60 million, RMB 310 million, RMB 470 million, RMB 700 million and RMB 910 million respectively.

As an upgraded version of Icotinib, the Furmonertinib from Allist reached a sales volume of RMB 232 million in the nearly seven months since its marketing approval in March 2021 until September 30.

Betta Pharmaceuticals landed on the STAR Market in November 2016 with Icotinib and Allist, a latecomer, landed on the STAR Market in December 2020 with Furmonertinib.

Can the Fourth Generation of EGFR-TKIs Create the Next Wealth Creation Myth?

Based on their strong wealth-creating ability, EGFR-TKIs have been a hot spot for capital chasing, and the R&D of the fourth generation of EGFR-TKIs is in full swing. The R&D of BLU-945 from Blueprint Medicines, CH7233163 from Roche, JNJ-372 from Johnson & Johnson and TQB3804 from Chiatai Tianqing is currently in full swing.

The targeting of the fourth generation of EGFR-TKIs is focused on combating Osimertinib resistance, in particular C797S resistance mutations, and the strategy is also through the development of targeting C797S, T790M/C797S, L858R/T790M/C797S or/and ex19del/T790M/C797S.

So, What Is the Market Outlook?

Population size: A 2019 paper specifically analyzed the resistance profile following Osimertinib resistance and found that the probability of C797S mutation was approximately 14%, compared to 7% in first-line dosing. It can be argued that the fourth generation of EGFR-TKIs are not desirable for a purely market-driven mindset.

Cost performance: The four generations of EGFR-TKIs currently in the public domain, in addition to the single-target C797S and dual-targeted T790M/C797S, there is also a category of L858R/T790M/C797S or/and ex19del/T790M/C797S, which is also an area of advantage for Osimertinib. The fourth generation of EGFR-TKIs also has to compete directly with the third generation of TKIs represented by Osimertinib. At that time, if the patent period of Osimertinib ends, the generic drug will take the stage. From an economic point of view, the drug of choice may not be the newly launched fourth generation of EGFR-TKIs.

External competition: Resistance after EGFR-TKI therapy is a current research hotspot, and in addition to the fourth generation of TKIs, combination regimen, monoclonal antibody, bispecific antibody, and ADC are also being explored for their efficacy against resistant mutations. For example, the ADC U3-1402, researches have revealed its potential therapeutic effect on patients with multiple EGFR-TKI resistance mechanisms, including C797S, MET amplification and HER2 mutations. It is evident that the fourth generation of EGFR-TKIs not only has to face the battle between their peers, but also has to guard against external "invasions".

It is evident that if the fourth generation of EGFR-TKIs is only positioned to solve the drug resistance problem and cannot replace the previous drugs, then their market size will not be as rosy as imagined. As to whether they can become the next wealth creation myth, I believe we all have the answer in mind.

References:

1.BrJ Cancer.2019;121:725-737；

2.Preclinical evaluation of TQB3804,a potent EGFR C797S inhibitor；　　3.Daiichi Sankyo announces clinical trial collaboration with AstraZeneca toevaluate patritumab deruxtecan(U3-1402)in combination with Tagrisso inEGFR-mutated non-small cell lung cancer.