Advances in the Treatment of Rare Epidermal Growth Factor Receptor Mutations in Advanced Nonsmall-Cell Lung Cancer

Abstract

Epidermal growth factor receptor (EGFR) mutations are common driver genes in nonsmall-cell lung cancer and have different sensitivities to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). EGFR is divided into classic mutations and rare mutations. Classic mutations are well known, but the understanding of rare mutations is not sufficient. In this article, we summarize the clinical research and treatment progress of rare mutations for different EGFR-TKIs and provide a basis for clinical treatment decisions.

Keywords

EGFR-TKIs EGFR mutations nonsmall-cell lung cancer (NSCLC)targeted therapy rare mutation

Introduction

Lung cancer is one of the leading causes of cancer-related deaths worldwide, with nonsmall-cell lung cancer (NSCLC) being the most common type. NSCLC-related driver genes include epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase, reactive oxygen species proto-oncogene 1, and cellular-mesenchymal epithelial transition factor, among which EGFR mutation is the most common gene mutation in NSCLC. Activating mutations in the EGFR gene occur in 10% to 20% of Caucasians and at least 50% of Asian NSCLC patients, especially in nonsmoking Asian women.¹ Several studies^2–7 have confirmed that compared with traditional chemotherapy, NSCLC patients with EGFR mutations are more sensitive to EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment, and the overall response rate (ORR) of EGFR-TKI treatment is >70%. The median progression-free survival (mPFS) is 9.6 months to 18.9 months, and the median overall survival (OS) is 21.6 months to 34.1 months.

The EGFR gene is located on the short arm of chromosome 7 (7p12-14), is approximately 118 kb long, and consists of 28 exons. The gene encoding the EGFR kinase domain is located in exons 18–25, and EGFR mutations in NSCLC patients mainly occur in exons 18–21. Mutation of the gene encoding the EGFR kinase domain leads to increased receptor kinase activity, so EGFR gene mutations are often referred to as EGFR activating mutations.⁸ EGFR mutations include common and rare mutations, exon 19 deletion (19del) and exon 21 point mutation (L858R) often referred to as classical EGFR mutations, together account for 85% of the EGFR mutations observed in NSCLC but are also highly sensitive to EGFR-TKIs.⁹ Rare mutations account for the remaining 15% of EGFR mutations in NSCLC, including point mutations, deletions, and insertions within exons 18–25 of the EGFR gene¹⁰ (Figure 1). Compared with classical mutations, some rare mutations have a poor response to EGFR-TKIs and poor clinical treatment effects. Although the proportion of rare mutations is low, accounting for only 15% of EGFR mutations, due to the high incidence of lung cancer, there are approximately 30 000 diagnoses worldwide each year. The number of patients in the real world is higher due to the limitations of current testing techniques and the difficulty in identifying rare mutations. However, there is still a lack of guidelines for the clinical management of patients with rare mutations. Here, we summarize the current treatment methods of common and rare mutations and related clinical studies and summarize and provide relevant clinical information to provide a reference for clinical treatment.

Figure 1.

Pie chart showing the frequencies of EGFR rare mutations in NSCLC. Data was acquired from COSMIC database.

Rare Mutation Types of EGFR

With the update and development of targeted drugs, more and more clinical trials and studies have found that different mutations have different sensitivity to different targeted drugs, and the sensitivity of some mutations to the same targeted drugs may also vary with different doses. We introduce its structural mechanism, different treatments, and related clinical studies according to the proportion of rare mutations in EGFR mutations from high to low.

EGFR Exon 20 Mutations

The EGFR exon 20 insertion mutation contains a heterogeneous insertion range of amino acids 1–7, which occurs at the C-terminal of the α C-helix. EGFR exon 20 insertion is the most common EGFR mutation in NSCLC except for exon 19del and L858R mutation. Its frequency is between 4% and 10% of all observed EGFR mutations, accounting for 16.85% of rare mutations.^11,12

The crystal structure of the EGFR exon 20 insertion mutant indicates that the insertion forms a wedge that “pushes” the α C-helix and prevents it from rotating outward into the inactive conformation, resulting in constitutive activation of the kinase domain. The insertion of exon 20 leads to significant structural changes in the P-ring and α C-helix, resulting in a relatively small drug-binding bag, which spatially hinders the first generation of EGFR-TKI binding.¹³

The patients with exon 20 insertion mutations had poor responses to the first- and second-generation TKI drugs. Previous studies have shown that^14–16 when receiving first- and second-generation EGFR-TKI treatment, the total effective rate of patients with insertion mutations in exon 20 was 0% to 11%, the mPFS time was 2–3 months, and the OS time was similar to that of wild-type EGFR patients. Robichaux et al¹³ expressed 7 different EGFR exon 20 insertion mutations in Ba/F3 cells. Dose–response experiments showed that the cells expressing EGFR exon 20 insertion mutations were sensitive to a low dose of poziotinib. At the same time, the phosphorylation of mutant EGFR decreased significantly after treatment with poziotinib (Table 1).

Table 1.

Clinical Outcomes of NSCLC Patients with Rare EGFR Mutations.

Mutation	Study （reference）	Mutation(s) included	N	EGFR-TKIs used	ORR (%)	DCR (%)	mPFS(mo)	mOS(mo)
Exon 20 insertion	Yang and coworkers¹⁴	Exon 20 insertions	23	Afatinib	8.7%	65.0%	2.7	9.2
	Tu et al.¹⁵	Exon 20 insertions	12	Gefitinib,Erlotinib	0%	NR	3.0	12.5
	Robichaux et al.¹³	Exon 20 insertions	44	Poziotinib	43.0%	NR	5.6	NR
	Fang et al.¹⁷	Exon 20 insertions	6	Osimertinib	66.7%	NR	6.2	NR
	Hasako et al.¹⁸	Exon 20 insertions	28	Mobocertinib	43%	NR	7.3	NR
G719X	Watanabe et al⁴	G719X	7	Gefitinib	14%	NR	NR	NR
	Yang and coworkers¹⁴	Single G719X (8), complex G719X mutations (6)	14	Afatinib	77.8%	NR	13.8	26.9
	Tu et al¹⁵	Single G719X (12), complex G719X mutations (4)	16	Gefitinib,Erlotinib	50.0%	NR	11.6	25.2
L861Q	Kobayashi et al¹⁹	L861Q	57	Gefitinib, Erlotinib	39.6%	75.5%	8,1	NR
	Kobayashi et al¹⁹	L861Q + G719X	9	Gefitinib, Erlotinib	88.9%	100%	NR	NR
	Yang and coworkers¹⁴	Single L861Q (12), complex L861Q mutations (4)	16	Afatinib	56.3%	NR	8.2	17.1
	Kobayashi and Mitsudomi¹⁰	L861Q	64	Gefitinib, Erlotinib	39.0%	77.0%	NR	NR
T790 M	Zhang et al²⁰	T790M	279	Osimertinib	71.0%	NR	10.1	NR
	Yang and coworkers¹⁴	Single T790M (3), Complex T790M mutations (11)	14	Afatinib	14.3%	NR	2.9	14.9
	Yun et al²¹	Del-19 or L858R + T790M mutations	9	Gefitinib, Erlotinib, Icotinib	22.2%	NR	1.94	16.89
	Mok et al²²	T790M	220	Furmonertinib	74.0%	94.0%	9.6	NR
	Shi et al²³	T790M	120	Almonertinib	68.4%	93.4%	11.2	NR
S768I	Ahn et al²⁴	Single S768I (1), complex S768I mutations (3)	4	Erlotinib	PD	NR	3.0	5.0
	Kobayashi and Mitsudomi¹⁰	S768I(12)	12	Gefitinib, Erlotinib	42.0%	58.0%	NR	NR
	Kobayashi and Mitsudomi¹⁰	complex S768I mutations (18)	18	Gefitinib, Erlotinib	53.0%	94.0%	NR	NR
	Yang and coworers¹⁴	Single S768I(1), complex S768I mutations(7)	8	Afatinib	100.0%	NR	14.7	NR
E709X	Leventakos et al²⁵	DelE709-T710insD (5), complex E709X mutations (13)	18	Gefitinib, Erlotinib	50.0%	72.2%	6.2	29.3
	Kobayashi and Mitsudomi¹⁰	DelE709-T710insD (4),	4	Gefitinib, Erlotinib	25.0%	50.0%	NR	NR
	Kobayashi and Mitsudomi¹⁰	complex E709X mutations (15)	15	Gefitinib, Erlotinib	53.0%	86.7%	NR	NR

Abbreviations: ORR, objective response rate; DCR, disease control rate; PFS, progression-free survival; OS, overall survival; NR, not reported; PD, progressive disease; mPFS, median PFS; mOS: median OS; NSCLC, nonsmall-cell lung cancer.

The preclinical studies of Lee et al²⁶ also showed that the third-generation EGFR-TKI osimertinib had a strong killing effect on exon 20 insertion mutant cells and wild-type EGFR cells, including the H773insH mutant. Subsequently, clinical studies by Fang et al¹⁷ confirmed for the first time that osimertinib has good antitumor activity in advanced NSCLC patients with insertion mutations in exon 20 (mPFS: 6.2 months). It can be concluded that patients with exon 20 insertion mutations may benefit more from treatment with the third-generation TKI osimertinib, but more clinical trials are needed.

For EGFR ex20ins mutations, different doses of the same drug will have different clinical effects. Studies have shown that TKI treatment for EGFR ex20ins mutations is dose-dependent. In a small phase II study in which patients with EGFR 20 insertion mutations were given osimertinib 160 mg/d, the results showed an ORR of 24% and PFS of 9.6 months. It is suggested that high-dose third-generation EGFR-TKIs may be effective in the treatment of exon 20 insertion mutations. In addition to osimertinib, several other compounds that inhibit insertion mutations in exon 20 have been studied in preclinical studies. TAK-788 is an irreversible inhibitor that selectively targets insertion mutations in exon 20. Based on the results of a phase I/II clinical trial, the U.S. Food and Drug Administration (FDA) has granted TAK-788 a breakthrough drug qualification for the treatment of EGFR ex20ins metastatic NSCLC patients. The results of the trial, reported at the online meeting of the American Association of Cancer Research 2020, showed that the objective remission rate (ORR) of TAK-788 (160 mg/d) in 28 patients with EGFR ex20ins mutations that could be evaluated was 43% (12max 28), and the mPFS was 7.3 months and was safe and controllable.¹⁸ CLN-081 (formerly TAS6417) is a new EGFR inhibitor (EGFRi). The ATP binding site of the mutant kinase inserted in exon 20 irreversibly binds to C797. Cell-free kinase analysis in vitro showed that compared with wild-type EGFR, TAS6417 was selective to D770N771; InSNPG. In a cell viability assay of human EGFR expressed by the Ba/F3 cell line, the inhibitory effect of CLN-081 on different EGFR ex20ins was stronger than that on wild-type EGFR, suggesting that it has good tolerance.¹⁸ In a cell experiment against EGFR ex20ins mutation in vitro, its IC₅₀ was only slightly smaller than that of poziotinib, but its selectivity index was much higher than that of other TKIs, indicating that it was more selective than poziotinib.²⁷

Different subtypes of exon 20 insertion mutations in NSCLC have significant heterogeneity and great differences in drug sensitivity. At present, third-generation TKIs have obvious benefits.

G719X

Among the rare EGFR mutations in NSCLC, G719X substitution (including G719S, G719A, G719C, and G719D substitution) is one of the more common mutations second only to exon 20 insertions, accounting for approximately 1.53% of all EGFR mutations in NSCLC and 13.78% of rare mutations.²⁸ G719X mutation can occur as an independent EGFR mutation, or it can be combined with other point mutations (such as S768I or L819Q). G719 is a phosphoric acid binding “P-ring” located in the N-leaf, which participates in the coordination of ATP by arching the triphosphate part.²⁹

Shan et al³⁰ predicted that the structural changes caused by the G719S mutation will also increase the tendency of dimerization and subsequent activation of EGFR in a manner similar to the classical L858R mutation. Yun et al³¹ demonstrated that any nonglycine residue at position 719 weakens the hydrophobic interaction that keeps the α C-helix in the inactive conformation, resulting in a 10-fold increase in kinase activity.

G719X mutation is highly sensitive to second-generation EGFR-TKIs. In preclinical studies, Kobayashi et al¹⁹ showed that the sensitivity of Ba/F3 cells expressing the G719A mutation in vitro to second-generation EGFR-TKIs was higher than that of first-generation EGFR-TKIs. They found that G719A was less responsive to gefitinib, erlotinib, and osimertinib than Ex19Del-expressing cells but sensitive to the second-generation EGFR-TKIs afatinib and neratinib, with IC₅₀ values of 0.9 and 1.1 nM, respectively. The results of clinical studies^4,15,16 showed that the first generation of TKIs was responsive to G719X mutation in NSCLC patients, but the sensitivity was slightly lower than that of classical mutation (ORR: 14%–53.3%, mPFS: 5.98–11.6 months, median OS: 16.4–25.2 months). The total effective rate of second-generation TKIs in the treatment of NSCLC patients with the G719X mutation was 75% and 77.8%, the mPFS was 12.1–13.8 months, and the median OS time was 26.9 months (Table 1). A postmortem analysis of the data of 32 patients from the LUX ‘Lung 2’ LUX ‘Lung 3 and LUX’ Lung 6 trials showed that afatinib had a clinical effect on the rare EGFR mutant (G719X ∼ S786I ∼ L861Q). In 8 patients with a single G719X mutation and 6 patients with a complex G719X mutation, 77.8% of RR and 13.8 months of PFS were treated with afatinib, which also expanded the indication of FDA in 2018 to include mutations in NSCLC patients with G719X. Therefore, it is recommended that second-generation EGFR-TKIs should be the first choice for advanced NSCLC patients with the G719X mutation.

L861Q

L861Q is located in the EGFR activation ring, accounting for approximately 3% of EGFR mutations in NSCLC and 9.88% of rare mutations.

L861Q stabilizes the conformation of active α C-helix in by forming a new H-bond near the C-terminal of the α C-helix and changes the sensitivity of L861Q to drugs by EGFR phosphorylation.²⁹

The L861Q mutation was highly sensitive to second-generation EGFR-TKIs and sensitive to osimertinib treatment. In a preclinical study, the study of L861Q in the Ba/F3 model system showed that L861Q was resistant to first-generation EGFR-TKIs compared with L858R. Chiu et al³² observed that its overall response rate (ORR) to first-generation EGFR-TKIs was 40%, indicating that it was moderately sensitive to S768I and G719X point mutations. This finding supports the preclinical observation that the L861Q mutation is less sensitive to the first generation of EGFR-TKIs than L858R. The LUX experiment LUNG³³ showed that afatinib treatment resulted in 12 patients with a single L861Q point mutation, 3 patients with L861Q/G719X, and 1 patient with a complex L861Q/Ex19Del mutation, with an RR of 56% and 8.2 months PFS. These data support the preclinical evidence that the L861Q mutation is sensitive to afatinib and led to FDA approval of afatinib for the treatment of L861Q mutation-positive NSCLC. The phase II clinical trial of osimertinib reported a partial response in 77.8% of patients with L861Q mutations (nyst9)²⁸ (Table 1). These data indicate that the L861Q mutation is sensitive to third-generation EGFRi and that osimertinib may be an effective treatment choice for patients with the L861Q mutation. At present, it is still considered that patients with the L861Q mutation will benefit more by choosing the second-generation TKI afatinib as the first choice.

T790 M

Yun et al²¹ found that the T790 M mutation can block the binding of ATP to the kinase region by changing the crystal structure of the ATP-binding pocket of the kinase region and increasing the affinity of TKIs, thus resulting in drug resistance. The sensitivity of the mutation to first- and second-generation EGFR-TKIs was low. Some studies^16,20,34 have shown that the mPFS time of patients with the T790 M mutation after first- and second-generation EGFR-TKI treatment is 1.4–2.9 months, and the median OS time is 14.9–16.89 months. Even if they coexist with sensitive mutations, Compound T790 M mutations are not sensitive to first- and second-generation TKIs. T790 M mutation is also considered to be the most common type of mutation in the mechanism of acquired drug resistance in the first and second generation of EGFR-TKIs. Some studies have used liquid biopsy analysis technology to find that³⁵ T790 M is the most common mutation among multidrug resistant mutations in patients with acquired resistance to first-generation and second-generation TKI drugs, and its drug resistance mechanism may be related to different methylation changes. Approximately 50% of patients with acquired drug resistance to TKIs have a secondary T790 M mutation.

However, with the emergence of third-generation TKIs, patients with secondary T790 M mutations have better survival outcomes. Phase III studies by Mok et al²² compared the efficacy of osimertinib and traditional chemotherapy in patients with T790 M drug-resistant NSCLC. The results showed that the osimertinib group was significantly better than the traditional chemotherapy group (ORR: 71% vs 31%, mPFS: 10.1 months vs 4.4 months), and the effect on patients with central nervous system (CNS) metastasis was better. Although it has been confirmed that osimertinib has a good effect on the T790 M mutation, it will show drug resistance again after a period of treatment, so the follow-up treatment of drug resistance of osimertinib remains to be further studied. Osimertinib is also the first approved drug in China for locally advanced or metastatic NSCLC with T790 M mutations in the first and second generation of TKI-acquired drug resistance. However, it is still not possible to determine the absolute efficacy of osimertinib in the treatment of T790 M, and further observations are needed.

In addition, preclinical studies have shown that furmonertinib and its active metabolite AST5902 have excellent antitumor activity and selectivity. A phase I dose increment study and a phase I/II dose amplification study showed that furmonertinib has clinical efficacy in advanced NSCLC patients with the EGFR T790 M mutation.³⁶ A phase IIb study reported²³ that advanced NSCLC patients with EGFR T790 M mutations (including CNS metastasis) had a PFS of 9.6 months after receiving furmonertinib, with an objective remission rate of 74% and a disease control rate (DCR) of 94%. In a summary analysis based on 2 II studies (the AURA extended study and the AURA2 study) and the AURA3 study,^22,24 the objective remission rates of osimertinib were 66% and 71%, respectively, while the disease control rates were 91% and 93% (Table 1), respectively. A phase II study showed³⁷ that the objective remission rate and DCR of almonertinib in Asian patients were 68.4% and 93.4%, respectively. Based on the excellent data of furmonertinib in the treatment of T790 M patients, a phase III study (NCT03787992) is underway to evaluate the first-line treatment of furmonertinib. These data suggest that furmonertinib can be recommended for advanced NSCLC patients with EGFR T790 M mutations who have developed resistance after first- or second-generation EGFR TKI therapy.

S768I

In addition to the insertion of exon 20, the point mutation S768I occurs in the region encoding the α C-helix in exon 20 of the EGFR gene, and its frequency is reported to be between 0.6% and 1% of all EGFR mutations, accounting for 6.39% of rare mutations.^7,10 S768I stabilizes the conformation of active α C-in by improving the hydrophobic packing between the α C helix and adjacent β 9 chains.

S768I has a high sensitivity to second-generation EGFR-TKIs, similar to L858R, but S768I is resistant to first- and third-generation EGFR-TKIs. Leventakos et al²⁵ confirmed that the S768I mutation was sensitive to first-generation EGFR-TKIs, but the sensitivity was very different (PFS: 3–20 months, OS: 5 months-51 months). Banno et al³⁸ showed that compared with L858R mutation, Ba/F3 cells expressing EGFR S768I were less sensitive to first- and third-generation EGFR-TKIs but more sensitive to the second-generation EGFR-TKI afatinib. In a postmortem analysis of the LUX “Lung 2” LUX “Lung 3 and LUX’ Lung 6 trials, the second-generation EGFR-TKI afatinib achieved 100% ORR in 8 patients with S768I mutant NSCLC and a mPFS, FDA of 14.7 months, thus approving the drug for use in NSCLC patients with EGFR S768I mutation (Table 1).

E709X

E709X point mutations accounted for <0.5% of all EGFR mutations.¹⁵ Due to the limitation of detection technology, the incidence of the E709X mutation is low, and because it is often combined with other mutations, there are few systematic studies on the relationship between the E709X mutation and the efficacy of TKIs. Studies by Wu et al³⁹ showed that the E709X mutation was sensitive to first-generation TKIs but slightly less sensitive than the classical EGFR mutation (ORR: 50.0% vs 74.1%). Although there is no large-sample clinical trial to prove the relationship between E709X and the efficacy of second-generation TKIs, Heigener et al⁴⁰ found that 10 patients with G719X mutations after first-line treatment failed for 2.6 months, while 4 patients with E709X mutations failed for 12.2 months, suggesting that E709X mutations may be more sensitive to the second-generation TKI afatinib (Table 1). The question is now whether patients with E709X mutations have the same benefits from different EGFR-TKI treatments, which needs to be further verified by a large sample size of clinical trials.

Compound Mutation

Compound mutation refers to the simultaneous detection of 2 or more different types of EGFR mutations in tumor cells of NSCLC patients, accounting for about 2.75% to 14% of all EGFR mutations.^15,41,42 EGFR compound mutations can be roughly divided into 3 types: biclassical mutations, coexistence of classical mutations and rare mutations, and coexistence of different rare mutations. Clinically, most rare mutations exist in the form of compound mutations. The response of patients with compound mutations to TKIs is very different, but all of them are weak. Xu et al³⁴ showed that the compound mutation with classical mutation and other rare mutations was more sensitive to TKIs than T790 M compound mutation with classical mutation (ORR: 55.6% vs 22.2%), and the sensitivity of double classical mutation to TKIs was the best of all compound mutations (ORR: 71.4%). Studies have confirmed that^43,44 after EGFR-TKI treatment, the prognosis of compound mutations with classical mutations and rare mutations is better than that with only rare mutations. Therefore, on the whole, the sensitivity of the three types of compound mutations to EGFR-TKIs from strong to weak is as follows: biclassical mutations, classical mutations with rare mutations, and only rare mutations. Chiu et al³² reported 19 cases of compound mutations with G719X mutations (G719X + L861Q, G719X + S768I). Studies showed that compound mutations had an ORR of 88.9%. At the same time, it is worth noting that the PFS of patients with compound mutations was significantly longer than that of patients with single mutations (11.5 months vs 6.3 months, Prun0.01). The mPFS of compound rare and rare mutation combinations was 5.1 months, while the shortest mPFS of single rare mutation PFS was 1.3 months and 2.6 months, respectively. These data suggest that complex mutations are more sensitive to EGFR-TKIs than single rare mutations, but the mechanism is unclear, and more clinical studies are needed.

EGFR-Kinase Domain Duplication

Wang et al⁴⁵ found that EGFR mutation kinase domain duplication (KDD) accounted for 0.12% of NSCLC and 0.24% of EGFR mutations, including typical rearrangements of exons 18–25 and rare rearrangements such as repeats of exons 14–26 and 17–25. Gallant et al⁴⁶ reported a 33-year-old male patient with advanced lung adenocarcinoma in 2015. The tumor puncture specimen was detected by next-generation sequencing (NGS). The results showed that the region of exons 18–25 of EGFR was continuously repeated without other EGFR mutations. The patient then received second-line afatinib targeted therapy after first-line chemotherapy combined with antiangiogenic therapy. The curative effect was partially relieved, and the disease progressed 7 months after treatment. The results of NGS sequencing of tissue samples after progression showed that the number of copies of KDD was higher than that before administration. At the same time, the results showed that EGFR-KDD was a tumorigenic factor because inhibition of EGFR-KDD could inhibit EGFR phosphorylation, EGFR tyrosine kinase activity, and downstream signal transduction. The third generation of TKI (erlotinib, afatinib, and AZD9291) could inhibit EGFR-KDD mutant cell lines, thus inhibiting EGFR phosphorylation and downstream signal transduction, but the effects of the three kinds of EGFR-TKI were different. The curative effect of afatinib is the best and most sensitive.

Immunotherapy for Rare Mutations of EGFR

At present, the treatment of new targets or cotarget mutations after targeted therapy resistance and drug resistance has become a difficult point in the next step of treatment, and immunotherapy can be considered as a therapeutic measure after targeted therapy resistance, and immunotherapy has initially shown efficacy in patients with rare EGFR mutations. In a retrospective analysis of the efficacy of immune checkpoint inhibitors (ICIs) in NSCLC patients with EGFR mutations, it was found that in patients with advanced NSCLC with EGFR mutations treated with ICIs, the objective response rate and DCR of those with uncommon EGFR mutations were higher than those with common EGFR mutations (71% vs 35. 7% and 57% vs 7%), the mPFS of those with less common EGFR synapses or no T790 M mutations was significantly longer than that of those with common EGFR mutations or T790 M mutations.⁴⁷ In another study, PFS was significantly longer in the immunosuppressant group than in the chemotherapy group in patients with EGFR mutations. (median, 9.7 months vs 6.1 months),⁴⁸ these suggest that immunotherapy may be a new treatment strategy for patients with rare EGFR mutations or poor responsiveness. However, for immunotherapy, there is a lack of limited immunotherapy efficacy markers and more clinical research, and the development of more effective markers for predicting immunotherapy efficacy may be one of the future research directions.

Conclusions

In summary, with the continuous development of molecular targeted therapy for rare driver genes such as EGFR ex20ins mutation, G719X, L861Q, S768I, etc, a variety of new antitumor drugs with rare driver genes have emerged, especially in the insertion mutation of exon 20, with the emergence of poziotinib, TAK.788, and JNJ.372 and the progress of clinical trials, NSCLC patients with EGFR ex20ins will have more and more choices in treatment. The rapid development of targeted therapy has brought dawn to NSCLC patients. Analyzing the efficacy of different EGFR mutation subtypes on targeted drugs is of great significance to guide clinical drug use. Because of the small sample size and high heterogeneity in patients with rare mutations in EGFR, the efficacy of EGFR-TKIs in patients with rare mutations in EGFR is still unclear. However, a large number of clinical studies over the years have shown that there are significant differences in the efficacy of TKIs in the treatment of NSCLC patients with rare mutations in EGFR, suggesting that we should analyze these patients separately in clinical studies and provide them with more effective individualized treatment.

Although the development of gene detection technology is changing with each passing day, most of the rare mutations in the clinic cannot be identified. At present, some studies have found that⁴⁹ liquid biopsy analysis can be used as an alternative method for EGFR detection in tumor tissues, for patients with positive or negative EGFR in tumor biopsies, but most of the fluid biopsy analysis in this study was carried out in patients with advanced NSCLC during TKI treatment, and its clinical application needs to be further improved. One urgent task is to develop and use gene detection methods that can more accurately identify different rare EGFR mutations as soon as possible. At the same time, prospective multicenter clinical studies and meta-analyses should be used to track the efficacy of EGFR-TKIs in NSCLC patients with rare EGFR mutations to provide more treatment options and clinical bases for the treatment of these patients.

Footnotes

Abbreviations

Acknowledgments

We thank the study patient and his family.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval

Not applicable, because this article does not contain any studies with human or animal subjects.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a project cosponsored by the Leading Talent Cultivation Project of Henan Health Science and Technology Innovation Talents (YXKC2020009), and the 51282 project Leading Talent of Henan Provincial Health Science and Technology Innovation Talents ([2016]32).

ORCID iD

Limeng Yu

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