Application of third-generation EGFR-TKI in EGFRm NSCLC treatment (Part I)

With the iterative update of lung cancer diagnosis and treatment technology, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have emerged one after
another.
Among them, the third-generation EGFR-TKI research layout covers the field of early-late treatment, bringing a new treatment option
to patients with EGFR-mutated non-small cell lung cancer (NSCLC).
On September 25, 2022, the CSCO Non-Small Cell Lung Cancer Expert Committee and the Expert Committee on the Safety Management of Antitumor Drugs published the first Expert Consensus on the Application of Third-Generation TKIs in the Treatment of EGFR-Mutated NSCLCs1.

Herein, Yimaitong will sort out the clinical research data of the third generation of EGFR-TKI and discuss the application
of the third generation of EGFR-TKI in the treatment of EGFRm NSCLC.

Modifying the mother ring and side chain, the third generation of EGFR-TKI successfully overcame the T790M drug-resistant mutation

The advent of the third generation of EGFR-TKI has broken through the first/second generation EGFR-TKI T790M mutation drug resistance barrier, and revolutionized the treatment pattern
of EGFRm NSCLC.
Different from the first/second generation EGFR-TKI with quinazoline as the parent ring structure, the third generation EGFR-TKI uses the pyrimidine ring as the parent ring structure, which overcomes the resistance of EGFR T790M and brings excellent efficacy and good safety
.

Taking the world's first third-generation EGFR-TKI osimertinib as an example, osimertinib uses pyrimidine as the mother ring, which has strong activity against EGFR-sensitive mutant tumor cells and weak activity against EGFR wild-type tumor cells, which effectively solves the problem
of severe adverse reactions caused by poor selectivity of first/second generation EGFR-TKI drugs 。 At the same time, osimertinib modified the side chain group to form a covalent bond targeting the ATP binding site of Cys-797 residues through unsaturated acryloyl chains, thereby irreversibly binding to the catalytic activity center of EGFR kinase, which successfully solved the problem
of T790M drug resistance.
In addition, osimertinib has also demonstrated good blood-brain barrier ^{penetration2,3}
.

There are two main active metabolites of osimertinib in vivo - AZ7550 and AZ5104
.
The activity and selectivity of AZ7550 and osimertinib are similar, while the activity of AZ5104 against EGFR-sensitive mutations and T790M drug-resistant mutations is 8 times higher than that of osimertinib, and the wild type also has a certain inhibitory effect
.
Ammetinib replaces the methyl group on the osimertinib indole ring with cyclopropyl, and its active metabolite HAS719 can inhibit the T790M drug resistance ^mutation4; Vometinib replaces the methoxy group on the osimertinib phenyl ring with trifluoroethoxypyridine, and its active metabolite AST5902 has antitumor activity and selectivity similar to the ^prototype5
.

Fig.
1 Molecular structure of third-generation EGFR-TKI

The value is highlighted, and the first-line treatment of third-generation EGFR-TKI has become the standard treatment

In April 2018, osimertinib was approved by the FDA for first-line treatment of EGFRm NSCLC patients, becoming the world's first third-generation EGFR-TKI approved for first-line treatment.
In August 2019, the first-line therapeutic indication of osimertinib was approved in China, marking that the first-line targeted therapy of EGFRm NSCLC patients in China has also entered the era of
"three generations in the same room".
The FLAURA study showed ^6,7 that osimertinib significantly prolonged median progression-free survival (mPFS) – 18.
9m vs.
10.
2m (HR=0.
46, P<0.
001) and median overall survival (mOS) – 38.
6m vs.
With 31 .
8m (HR=0.
80, P=0.
046), osimertinib is currently the only* EGFR-TKI
with overall survival benefit.
The FLAURA Chinese cohort study included 136 Chinese patients randomized to receive osimertinib (n=71) or EGFR-TKI (n=65).

The final analysis showed that patients treated with first-line osimertinib extended mPFS for 8 months (17.
8m versus 9.
8m) and mOS by 7.
4 months (33.
1 m versus 25.
7 m) compared with first-generation EGFR-TKIs
.
At present, authoritative guidelines at home and abroad recommend osimertinib as the standard first-line treatment for patients with EGFRm NSCLC, of which NCCN guidelines are preferred, ESMO guidelines are IA and the highest level recommendations, and CSCO guidelines are level I recommendations ^8-10
.

Fig.
2 PFS (left) and OS (right) of osimertinib in the first-line treatment of the whole population

At the 2021 ASCO conference, ametinib announced the results of a Chinese multicenter AENEAS study for the first-line treatment of
EGFRm NSCLC patients.
The results of AENEAS ^studies11,11 showed significantly longer mPFS in first-line patients treated with ametinib (19.
3m vs.
9.
9m, HR=0.
46, p<0.
0001) compared with gefitinib.

OS data is not yet mature (maturity level is 29%), OS HR=0.
82 (P=0.
28), no OS benefit trend has been seen, and the final OS results are yet to be revealed
.

Fig.
3 PFS of ametinib in the first-line treatment of the whole population

The results of the FURLONG study showed ¹², compared with gefitinib, the first-line treatment of vometinib with EGFRm NSCLC significantly prolonged mPFS (20.
8m vs.
11.
1 m, P<0.
0001) and reduced the risk of<b20> disease progression or death by 56%.
。 OS data is not yet mature (maturity level is 32%), OS HR=0.
94 (P=0.
7446), no OS benefit trend has been seen, and the final OS results are yet to be revealed
.

Fig.
4 PFS of the whole population in the first-line treatment of vometinib

Lasting benefits, third-generation EGFR-TKI second-line therapy helps patients move towards long-term survival

Second-line studies, represented by the AURA series, have established the standard status
of osimertinib in patients with EGFR T790M mutation resistance.
The results of the global multicenter randomized controlled phase III clinical study AURA3 showed that osimertinib compared with platinum combined with pemetrexed dual-agent chemotherapy regimen had PFS of 10.
1 months and 4.
4 months (HR=0.
30, P<0.
001)<b20> in patients with T790M mutations after EGFR-TKI treatment, respectively 。 It is worth mentioning that the real-world study of osimertinib second-line treatment of Chinese patients, ASTRIS China cohort data was also released at the 2022 WCLC, and the results showed that the Chinese group received osimertinib second-line treatment had an ORR of 55.
7% and mPFS of 11.
7 months, of which tissue testing T790M positive patients had mPFS for up to 13.
1 ^months14 The results of the Chinese subgroup were highly consistent with the total population of ASTRIS and previous clinical studies, reconfirming the significant benefits
of osimertinib for Chinese patients.

In the phase II APOLLO study, the ORR of ametinib second-line EGFR T790M NSCLC patients was 68.
9% and mPFS was 12.
4 ^months15
.
The ALSC003 study evaluated the efficacy and safety
of vometinib in patients with T790M mutation NSCLC after progression after first/second generation EGFR-TKI treatment.
Results showed an ORR of 74% for T790M-positive patients and an mPFS of 9.
6 months16
.
Based on the data of the above-mentioned phase II single-arm clinical study, ametinib and vometinib were approved for conditional marketing in
China.

Facing brain metastasis, the third-generation EGFR-TKI has a significant effect on the treatment of lung cancer brain metastasis

The central nervous system (CNS) is one of the most common metastases in NSCLC patients, and once lung cancer has brain metastasis, patients have a poor prognosis and short
survival.
Drug treatment is one of the important treatment methods for NSCLC with brain metastasis, and compared with the first generation of EGFR-TKI, the third generation of EGFR-TKI has a stronger ability to penetrate the blood-brain barrier and the concentration of the drug into the brain is higher
.
Preclinical data showed that the peak concentration ratios of brain tissue to plasma of osimertinib, gefitinib and afatinib were 3.
41, 0.
21 and <0.
3617
, respectively.
Ammetinib and vometinib can also penetrate the blood-brain barrier and are well distributed in brain ^tissue5,18
.

At present, all three third-generation EGFR-TKIs have published efficacy data on brain metastases, but it is worth noting that the FLAURA study used CNS PFS as a key secondary endpoint, and the results were conclusive and statistically powerful; The AENEAS and FURLONG studies used CNS PFS as an exploratory endpoint
.
The results of the FLAURA study showed that in patients with baseline with brain metastases, mPFS in patients receiving osimertinib was significantly prolonged compared with first-generation EGFR-TKI (15.
2m vs.
9.
6m, HR=0.
47); In addition, osimertinib significantly reduced the risk of CNS progression or death by 52% (CNS mPFS: NR vs.
13.
9m, HR=0.
48) and reduced the occurrence of new CNS lesions (30% vs.
12%)^6,19, suggesting that first-line treatment with osimertinib significantly prolongs CNS PFS and reduces CNS progression
。 To date, the FLOURISH study, the largest real-world study of osimertinib first-line treatment in China, suggests that patients can benefit from first-line treatment of osimertinib regardless of whether they have brain metastases at baseline: in the population with brain metastases at baseline, ORR and DCR are 60.
0% and 95.
0%, respectively, and the one-year PFS rate is 78.
9%; In patients without brain metastases at baseline, ORR and DCR were 60.
0% and 97.
5%, respectively, and the 1-year PFS rate was 77.
7%²⁰
。 ADAURA studies also support osimertinib to reduce the risk of CNS recurrence, and the ADAURA results updated at the 2022 ESMO conference showed that adjuvant treatment with osimertinib in patients with classic mutations in stage IB-IIIA EGFR and NSCLC after complete resection reduced the postoperative CNS recurrence rate (osimertinib 6% vs.
control group 11%)
.
In patients with stage II-IIIA, osimertinib reduced the risk of CNS recurrence or death by 76% compared with ^controls21
.
The AURA3 study showed that second-line treatment of osimertinib in patients with EGFR T790M NSCLC prolonged CNS mPFS (11.
7m vs.
5.
6m, HR=0.
32, P=0.
004) and increased CNS ORR (70% vs.
31%) ^{compared with chemotherapy22}
.

Fig.
5 mPFS (left) and CNS mPFS (right) of patients with baseline brain metastases in the FLAURA study

The AENEAS study showed that first-line ametinib prolonged mPFS compared with gefitinib in patients with brain metastases at baseline (15.
3m vs.
8.
2m, HR=0.
38, P<0.
0001); CNS mPFS(29.
0m vs.
8.
3m, HR=0.
319; P<0.
0001)^11,23
.
The APOLLO study showed that the mPFS of EGFR T790M NSCLC with CNS metastases was 11.
8 months and the CNS ORR was 60.
9% in second-line treatment of EGFR T790M NSCLC^{, 15}
.

Fig.
6 mPFS (left) and CNS mPFS (right) in patients with baseline brain metastases in AENEAS study

Data from the CNS metastasis subgroup in the FURLONG study showed that the first-line treatment of vometinib significantly prolonged mPFS (18.
0m vs.
11.
2m, HR=0.
514, P=0.
0028) and prolonged CNS mPFS (20.
8m vs.
9.
8m, HR=0.
40, P=0.
0011) compared with gefitinib.
Post-hoc analysis of patients without baseline CNS metastases showed no new CNS metastases in the vometinib group, compared with 8 in the gefitinib ^group12,14
.
Another study of vometinib second-line EGFR T790M NSCLC showed that vometinib treated CNS PFS for 11.
6 months and CNS ORR of 66% in patients with CNS metastases16
.

Fig.
7 CNS mPFS in patients with baseline brain metastases in the FURLONG study

Third-generation EGFR-TKI first-line combination therapy is expected in the future

In recent years, the exploration of first-line combination therapy strategies for EGFR-TKI has been
in full swing.
The WJOG9717L study explored the efficacy and safety of osimertinib plus bevacizumab versus osimertinib monotherapy in the first-line treatment of advanced NSCLC, and showed that the median PFS was similar in both groups (22.
1m vs.
20.
2m, HR=0.
862, P=0.
213), and no new safety signals occurred in the osimertinib plus bevacizumab ^group25
。 At the 2022 ASCO conference, OPAL Research was the first to announce the results
of osimertinib combined with chemotherapy for the first-line treatment of EGFRm NSCLC patients.
The results showed that the ORR of patients receiving cisplatin/carboplatin + pemetrexed + osimertinib first-line treatment with NSCLC was 90.
9%, the PFS rate at 12 months was 90.
4%, the PFS rate at 24 months was 70%, and the OS rate at 24 months was 92.
3% ²⁶
.
The ongoing first-line osimertinib combination chemotherapy study (FLAURA2), the first-line ametinib combination chemotherapy study (NCT04923906), and the first-line vometinib combined chemotherapy study (FOCUS-C) data are expected to be announced.

Fig.
8 ORR of osimertinib combined with chemotherapy in the first-line treatment of NSCLC patients in OPAL study

Third-generation EGFR-TKI drug resistance mechanism and follow-up treatment regimen exploration

Third-generation EGFR-TKIs have been widely used in the first-line treatment of EGFRm NSCLC patients, but drug resistance is still unavoidable
.
In the global exploration of the problem of third-generation EGFR-TKI drug resistance, the resistance mechanism and corresponding drug resistance strategy of osimertinib are relatively clear
.
Studies have shown that common drug-resistant mutations of osimertinib include MET amplification, C797X mutation, histological transformation^{, etc.
27.}

For the resistance of osimertinib, some promising treatment options have been explored, such as the ORIENT31 study, which showed that the PD-1 immunosuppressant ±bevacizumab combined with chemotherapy can significantly prolong PFS 28 in patients with NSCLC who have failed EGFR-TKI therapy
。 For MET amplification after drug resistance, third-generation EGFR-TKI+MET-TKI may be a potential treatment option; For the C797X mutation, some promising drugs such as BBT-176 have shown good activity in preclinical trials and have entered the clinical trial stage; For small cell lung cancer transformation, chemotherapy ± immunotherapy has shown good results in clinical ^studies29
.
The exploration of second-line resistance to ametinib and vometinib found that C797X mutation was the most common secondary mutation
of EGFR.
In addition, common drug-resistant mutations in ametinib include mutations in the phosphatidinositol kinase-3 catalytic α (PIK3CA) ^gene30; Common resistance mechanisms of vometinib include HER2 gene amplification, ERBB2 amplification, and MET ^{amplification16}
.
At present, the drug resistance mechanism of ametinib and vometinib and their corresponding drug resistance strategies are still being explored, and it is expected to bring a clearer drug resistance mechanism and more post-drug resistance solutions
to drug-resistant patients in the future.

brief summary

The development of the third-generation EGFR-TKI targeted drug has brought new benefits to EGFRm NSCLC patients, and the drug regimen
should be selected in real clinical practice, such as drug efficacy, drug toxicity, and patient physical function.
It is expected that more real-world clinical data will be generated in the next three generations of EGFR-TKI, providing solid evidence for clinicians' diagnosis and treatment, and benefiting more lung cancer patients
.
The next part will introduce the healing path of the three generations of EGFR-TKI in early and mid-term NSCLC, so stay tuned!

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