From EGFR-TKI iteration to see the dynamic changes of lung cancer clinical needs

Article source: Med

Author: Leaf

In China, lung cancer is the malignant tumor with the highest morbidity and mortality, and new cases are still on the rise

Among them, EGFR-TKI is a sign that lung cancer treatment has gradually entered the era of targeted therapy from the era of chemotherapy

Important milestones in the development of EGFR-TKIs

Gefitinib, Erlotinib

In 1962, Stanley Cohen et al.

The EGFR gene is located on chromosome 7p12-13 and encodes a receptor tyrosine kinase protein with a length of approximately 170kDa

Overview of EGFR mutations in NSCLC (Source: Seminars in Cancer Biology 61 (2020) 167–179)

Looking back, the development of EGFR-TKI is not as natural as it seems now, and it is also inseparable from the creative exploration of Asian clinicians including Professor Tony Mok and Professor Wu Yilong

Erlotinib at this time, although the combination of platinum chemotherapy (carboplatin + paclitaxel or gemcitabine + cisplatin) did not show clinical benefits for the NSCLC population, it was obtained before gefitinib was asked to delist.

Gefitinib/erlotinib sales in the past ten years

In 2004, the discovery of EGFR mutations in lung cancer and the subsequent significant efficacy of EGFR-TKI in retrospective analysis and small phase II studies paved the way for a paradigm shift in clinical trials

Now, we already know that the reason for this difference in results is the different frequency of EGFR mutations in Chinese and Western patients

However, the golden age of gefitinib is limited

Compared with the first-generation drugs, the second-generation drugs afatinib and dacomitinib have directly come to the first-line treatment of patients with EGFR-mutant NSCLC in terms of indications, and have shown unique potential

It is not difficult to see that gefitinib and erlotinib have deduced the concept of precision therapy and opened the door to targeted therapy for patients with EGFR-mutant NSCLC

Three generations of EGFR-TKI represented by Osimertinib

The successive approvals of the first and second generation EGFR-TKIs and the expansion of indications have brought major breakthroughs in clinical treatment, but also brought new challenges

In 2005, when the application prospects of the first-generation EGFR-TKI were not completely clear, in the biopsies of TKI-resistant patients, researchers discovered the secondary EGFR resistance mutation EGFR T790M

In 2009, AstraZeneca started the third-generation EGFR-TKI research

From the beginning of clinical research in 2013 to the approval for the treatment of EGFR T790M mutant NSCLC patients in November 2015, it will gradually be approved globally for first-line medication for EGFR mutation patients in 2016

Sales of osimertinib over the years

Along the indication path and development strategy of osimertinib, Ametinib and Vometinib were successively approved for marketing by NMPA, and in the head-to-head study of Gefitinib, positive data for first-line treatment was obtained

Differences in overall survival of EGFR-TKIs with different treatment strategies (Source: Mol Cancer.
2018; 17: 29)

From the perspective of cost performance, gefitinib has been included in centralized procurement, and the drug price is more accessible
.
For patients whose treatment is progressing, with the dynamic adjustment of medical insurance negotiations, there is a high probability that osimertinib can be treated sequentially, and the overall survival of the patient can also be guaranteed
.
From the perspective of clinical effectiveness, osimertinib has already outperformed gefitinib in head-to-head studies.
There is not much difference between osimertinib directly in the first-line and sequential osimertinib after the first and second generation EGFR-TKIs.
, And even the earlier the use of osimertinib in the overall survival period, the better; and from the consideration of drug tolerance, different patients can adopt differentiated treatment strategies
.

EGFR-mutant lung cancer treatment plan

EGFR-TKIs，
。，EGFR-TKIs
。，，
。Met、PIK3CABRAFKRAS，Exon20
。，、NSCLC
。，，EGFR C797S
。

（：Bridge Biotherapeutics）

，EGFRC797S
。，EGFR-TKIsC797S
。EGFR-TKIs，，EGFR-TKI
。

，C797S，TKIC797S，
。T790M/C797S，EGFR-TKI；，，
。C797S，，
。，，Amivantamablazertinib、patritumab deruxtecan
。

C797S mutation treatment strategy (Source: Br J Cancer.
2019; 121(9):725-737)

However, after the third generation of EGFR-TKI, there is a huge unmet need for personalized precision treatment.
The difficulty is that there are too few problems that a drug can solve
.
Among them, the C797S mutation is the basis for the development of the fourth-generation EGFR-TKI drugs
.

Fourth-generation EGFR and degradants

BLU-945 and BLU-701 are two fourth-generation EGFR-TKIs developed by Blueprint Medicines.
Recently, Zai Lab received US$25 million in advance and a maximum of US$590 million in Greater China rights
.
BLU-945 is the fourth-generation EGFR-TKI clinical research drug that discloses the most detailed preclinical data
.
Pre-clinical data show that BLU-945 and BLU-701 both have central system activity, and about 20% of patients with stage IV NSCLC have brain metastases; in addition, the first indication of the fourth-generation EGFR-TKI will also be highly probable.
It is second-line or posterior-line NSCLC treatment, and having central activity can always gain a lot
.

Interestingly, BLU-701 is the fourth-generation EGFR-TKI that Blueprint is the first to publish preclinical data, but BLU-945 has advanced to clinical development earlier
.
Perhaps, this is also the choice made by Blueprint after considering the clinical dynamics
.
Preclinical data shows that BLU-945 has better target activity potential and second-line clinical treatment advantages than BLU-701
.
However, if you want to impact the first-line treatment of EGFR-mutant NSCLC, the combination of BLU-945 and BLU-701 seems to be a better choice
.
Perhaps this is also the consideration for Zai Lab to introduce the rights and interests of two drugs at the same time
.

BLU-945/BLU-701 preclinical data and potential application scenarios (Source: Blueprint Medicines)

Degradation of EGFR protein seems to provide a "one-and-for-all" solution.
Unfortunately, the progress of such drugs is slow
.
Currently, only CFT8919 developed by C4 Therapeutics in the world has published preclinical data
.
In terms of data, CFT8919 achieves better target selectivity and can show efficacy against a variety of EGFR mutation types, including L858R, T790M, C797S, and rare EGFR mutations
.

CFT8919 cell viability data (Source: C4 Therapeutics)

For EGFR L858R patients, the therapeutic benefits of the marketed EGFR-TKIs are generally lower than those of patients with EGFR ex19del mutations
.
Therefore, the performance of CFT8919 in this group is worth looking forward to
.
At the same time, CFT8919 also has the potential for treatment from the back line to the first line, and C4 Therapeutics is positioned in this way
.
However, CFT8919 has not disclosed preclinical data for ex19del mutation, or it will lose about 45% of EGFR-mutant NSCLC patients
.

CFT8919 treatment scenario (Source: C4 Therapeutics)

On November 19, the "Guiding Principles for Clinical Research and Development of Anti-tumor Drugs Oriented by Clinical Values" was formally implemented, with special attention to the dynamic changes in treatment needs and the applicable scenarios of single-arm research
.
After the launch of three third-generation EGFR-TKIs targeting EGFR T790M mutations, especially after the gradual increase in the availability of medicines through medical negotiations, can the "back wave" third-generation EGFR-TKIs who continue to apply for listing on the condition of single-arm research? Obtaining the approval of the regulatory authorities will become the most direct challenge
.
In addition, for the fourth-generation EGFR-TKI to realize its clinical value, what drug potentials should be possessed, what development strategies should be adopted, and the dynamic changes in clinical needs should also be pursued
.

The market will not hesitate to return only if drugs that truly meet clinical needs
.
Throughout the iterative history of EGFR inhibitors, it is not so
.

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