The third-generation EGFR inhibitor in the targeted therapy series for non-small cell lung cancer (NSCLC) (1)

Non-small cell lung cancer (NSCLC) remains the most common malignancy among lung cancers, resulting in an increasing mortality rate in recent years
.

Non-small cell lung cancer accounts for more than 80% of lung cancers, and the vast majority of patients are found in advanced inoperable stages
.

Chemotherapy used to be the mainstay of treatment for non-small cell lung cancer, but due to its significant side effects
.

Chemotherapy gradually withdrew from the stage of history
.

In recent years, cellular and molecular biotechnology has developed rapidly, and researchers have begun to target key genes and regulatory molecules for treatment
.

Targeted drugs also emerged
.

Generally speaking, targeted drugs can be divided into two categories
.

One class is targeting tumor angiogenesis, including anti-vascular endothelial growth factor and endostatin monoclonal antibodies
.

They inhibit angiogenesis and growth, which in turn reduces endothelial cell metastasis
.

The other is the small molecules that act on the signal transduction pathway of tumor cells, and they inhibit the growth of tumors by inhibiting signal transduction
.

Before starting targeted therapy, patients must undergo genetic sequencing to determine their genotype
.

Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are currently the most common mutated targets in NSCLC, and several generations of targeted drugs have been developed against EGFR and ALK to overcome drug resistance
.

This series gives a brief introduction to the third-generation targeted drugs targeting EGFR and ALK
.

EGFR is a member of the ErbB family of receptor tyrosine kinases
.

Activated EGFR can stimulate PI3K-AKT-mTOR, STAT, MAPK and other pathways through signal transduction, ultimately leading to cell proliferation and tumorigenesis
.

Most non-small cell lung cancer patients have EGFR mutations, and the most common EGFR mutations are 19del and L858R
.

The T790M exon mutation was mainly associated with drug resistance mutations
.

Figure 1 illustrates the transduction process of EGFR signaling
.

When EGFR-TKI acts on EGFR targets, it can inhibit the transmission of downstream signaling
.

Figure 1.
Transduction process of EGFR signaling The first-generation EGFR-TKIGefitinib (gefitinib), erlotinib (erlotinib) and icotinib (icotinib) are the first-generation EGFR-TKIs, and they are all reversible
.

Gefitinib was approved as a first-line drug by the U.
S.
Food and Drug Administration (FDA) in 2015
.

Its clinical study is called IPASS
.

In 1998, phase I clinical studies of gefitinib showed good drug resistance and efficacy
.

Preliminary results from 1692 patients enrolled in the 2004 ISEL study showed that gefitinib prolonged progression-free survival (PFS)
.

Since then, China, Japan, Singapore and other Asian countries have successively carried out IPASS Phase III studies
.

This is the first large randomized controlled trial to compare gefitinib with carboplatin and paclitaxel
.

A total of 1217 patients with adenocarcinoma were divided into two groups, one group was oral gefitinib 250 mg/d, the other group was oral carboplatin + paclitaxel
.

The primary endpoint was progression-free survival (PFS)
.

Secondary endpoints included overall survival (OS) and adverse events
.

The final results showed that the PFS (9.
5 vs 6.
3 months) and ORR (71.
2% vs 47.
3%) of gefitinib were higher than those of the chemotherapy group (Table 1)
.

Gefitinib has been shown to be more effective than chemotherapy
.

Table 1.
Comparison of EGFR-TKI and first-line chemotherapy.
The comparison of erlotinib with carboplatin and gemcitabine was studied in OPTIMAL in China
.

The PFS in the erlotinib group and chemotherapy group was 13.
1 months and 4.
6 months, respectively, and the effective rate in the erlotinib group was as high as 83%, while the effective rate in the chemotherapy group was only 36% (Table 1)
.

As the first controlled study of erlotinib, the OPTIMAL study has the same important status as the IPASS study
.

The Western EURTAC study also compared erlotinib with chemotherapy
.

The PFS was 9.
7 months and 5.
2 months in the two groups, respectively, and the advantage of erlotinib was the same
.

The CONVINCE study was a first-line comparative chemotherapy study of icotinib
.

In this study, PFS was longer in the icotinib arm than in the chemotherapy arm (11.
2 months vs.
7.
9 months), and adverse effects were also reduced (54.
1% vs.
90.
5%)
.

The CONVINCE study is the first to demonstrate that icotinib is more beneficial than chemotherapy, establishing lcotinib as a first-line treatment
.

First-generation EGFR-TKIs have better clinical benefit than standard chemotherapy in both PFS and ORR
.

Therefore, first-generation EGFR-TKIs are increasingly approved for first-line therapy
.

Some researchers have conducted comparative studies of first-generation targeted drugs to determine the best drug treatment regimen
.

In the CTONG 0901 study, 256 patients with advanced non-small cell lung cancer with EGFR exon 19 or 21 mutations were randomized to receive erlotinib or gefitinib and compared PFS and OS
.

The results showed that the PFS and OS of the erlotinib and gefitinib groups were 13.
2 vs 11.
1 months and 22.
4 vs 20.
7 months, respectively
.

Unfortunately, the CTONG 0901 study was not continued and did not definitively establish the clinical efficacy of erlotinib over gefitinib
.

Another study, ICOGEN, compared the efficacy and safety of icotinib and gefitinib in second- and third-line treatment of advanced non-small cell lung cancer
.

PFS for icotinib and gefitinib was 7.
8 and 5.
3 months, respectively; OS was 20.
9 vs.
20.
2 months (Table 2)
.

In this study, the results of PFS and OS were similar, but the adverse effects of icotinib were lower than those of gefitinib in terms of safety (60.
5% vs.
70.
4%), which may be related to the high selectivity of icotinib
.

Analysis of these two studies showed that the three first-generation EGFR-TKIs did not differ significantly in prolonging PFS and were similar in adverse effects
.

Table 2.
Comparison of clinical trials of EGFR-TKIs Second-generation EGFR-TKIs First-generation EGFR-TKIs have benefited patients, but drug resistance persists
.

Second-generation EGFR-TKIs are irreversible drugs that have more targets than first-generation EGFR-TKIs and therefore have greater side effects
.

In the LUX-Lung 3 study, compared with cisplatin and pemetrexed, PFS was 11.
1 months in the afatinib group and 6.
9 months in the chemotherapy group (Table 1)
.

Based on this study, afatinib was approved as a first-line drug
.

In the LUX-Lung 6 study, afatinib was compared with the gemcitabine/cisplatin chemotherapy arm, and the PFS was 11.
0 months and 5.
6 months, respectively (Table 1)
.

Although PFS was significantly prolonged in the LUX-Lung 3 and LUX-Lung 6 studies, there was no significant difference in OS compared with the chemotherapy group
.

In the LUX-Lung 7 study, afatinib and gefitinib were similar in terms of PFS (11.
0 vs 10.
9 months) (Table 2)
.

From the comparative analysis of CTONG 0901, ICOGEN and LUX-Lung 7, there was no significant difference in efficacy and safety of first- and second-generation EGFR-TKIs in terms of PFS, OS and safety
.

Another second-generation EGFR-TKI, dacomitinib (dacomitinib), was compared in first-line with gefitinib in the ARCHER-1050 study
.

The results showed that the PFS of dacomitinib and gefitinib were 14.
7 months and 9.
2 months, respectively
.

Although dacomitinib led the way in PFS, 66.
5% of patients required dose adjustment due to toxicity (Table 2)
.

 Third-generation EGFR-TKIs With the use of first- and second-generation EGFR-TKIs, most patients developed drug resistance, mainly due to mutations in exon T790M (exon 20)
.

Therefore, researchers focused on second-line treatment, and the third-generation EGFR-TKI Osimertinib (Osimertinib) emerged
.

Osimertinib is an irreversible tyrosine kinase inhibitor that inhibits the T790M mutation
.

The AURA series of studies was an evaluation of the efficacy and safety of osimertinib
.

In the AURA3 phase III study, osimertinib was used to treat T790M-resistant patients and was compared with cisplatin/pemetrexed
.

The results showed that PFS 10.
1 vs 4.
4 months, ORR 71% vs 31%
.

Importantly, the intracranial ORR of osimertinib was 70%, which was associated with the prevention of cancer metastasis (Table 1)
.

Based on this study, osimertinib is approved for second-line treatment of EGFR T790M mutation
.

The excellent performance of osimertinib in second-line therapy provided additional survival benefit in patients with T790M mutation
.

Later, researchers focused on first-line treatments
.

In the FLAURA study, first-line treatment with osimertinib was compared with the standard arm of first-generation EGFR-TKIs
.

Osimertinib significantly improved PFS (18.
9 vs 10.
2 months) and was well tolerated
.

In addition, patients did not have the T790M mutation, and the most common resistance mechanisms were MET amplification and C797S mutation (Table 2)
.

The results of the FLAURA study fully demonstrate the status of osimertinib in first-line treatment, and first-line PFS and OS are superior to first- and second-generation EGFR-TKIs
.

Based on this study, osimertinib was approved by the FDA for first-line treatment
.

Of course, osimertinib will inevitably develop resistance
.

Schoenfeld et al.
sequenced patients with EGFR-mutant lung disease treated with osimertinib before and after treatment
.

Histological changes, mainly squamous, were found in 15% of initial patients and 14% of treated patients
.

Off-target mutations occurred in 19% of first-line patients
.

References 1.
Breakthrough in targeted therapy for non-small cell lung cancer.
2.
Overcoming therapy resistance in EGFR-mutant lung cancer.
3.
Amivantamab for the treatment of EGFR exon 20 insertion mutant non-small cell lung cancer.