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. 2020 Jun 28;146(9):2329–2338. doi: 10.1007/s00432-020-03296-6

Non-small cell lung cancer patients with ex19del or exon 21 L858R mutation: distinct mechanisms, different efficacies to treatments

W-Q Li 1, J-W Cui 1,✉
PMCID: PMC11804701  PMID: 32596787

Abstract

With the development of antitumor therapies, different treatment methods including monotherapy and combined therapy have achieved clinical efficacy in advanced epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) patients. Exon 19 deletion (ex19del) and exon 21 L858R mutation are common sensitive subtypes of EGFR mutation. However, potential distinct mechanisms are found from several dimensions including molecular structures, biological behaviors, concomitant mutations, resistance mechanisms and tumor mutation burdens. More evidence indicates the prognostic difference of EGFR subgroups. This review focused on the progress of potential distinct mechanisms and outcomes in clinical trials of advanced NSCLC patients with ex19del or exon 21 L858R mutation.

Keywords: Epidermal growth factor receptor, ex19del, Exon 21 L858R mutation, Non-small cell lung cancer

Overview

Lung cancer is the most common cause of cancer death. Non-small cell cancer (NSCLC) is the major histological categories of lung cancer, which occurs approximately 85% of cases (Siegel et al. 2019; Roskoski 2019; London and Gallo 2020). With the development of epidermal growth factor receptor (EGFR) mutation detection and its targeted therapy, there is a noticeable rise in the survival of advanced NSCLC patients, with a median overall survival (OS) of 38.6 months in single-agent third-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) and 50.9 months in combination therapy (Ramalingam et al. 2020; Hosomi et al. 2020). However, the mutation rate of EGFR gene varies among countries and ethnicities, which is approximately 50% in Asian patients while only 10–20% in Caucasian patients (Zaric et al. 2014; Harrison et al. 2020). Although there are different types of EGFR mutations, approximately 90% are mutations harboring exon 19 deletion (ex19del) or exon 21 mutation, and L858R mutation is the predominant subtype of exon 21 mutation (Lee 2017; Wang and Li 2019). In spite of both mutations are sensitive to EGFR-TKIs, increasing studies confirmed their differences in therapeutic effects and the optimal therapeutic regimen remains indeterminate (Cross et al. 2014; Riely et al. 2006; Castellanos et al. 2017). This review aimed to explore the distinct potential mechanisms and therapeutic efficacy of advanced NSCLC patients with ex19del and exon 21 L858R mutation to provide optimal first-line treatment strategies for clinical decision.

Distinct mechanisms of sensitive EGFR subtypes

Patients with different EGFR subtypes have specific EGFR-TKI therapeutic effect for the following potential mechanisms. First of all, tracing the difference of molecular structures is fundamental. Ex19del represents in-frame deletions contained amino acid residues 746–750 of the expressed protein while L858R mutation is a single-nucleotide substitution that replaced leucine with arginine at codon 858 (Kumar et al. 2008). EGFR tyrosine kinase domain was comprised of N-terminal lobe, C-terminal lobe and active ATP site lying in the cleft of two lobes (Massarelli et al. 2013). Both of existence of ex19del and L858R mutation could reduce the affinity for ATP and the competition for binding sites, lead to an increased receptor dimerization and activity (Reguart and Remon 2015). Distinctively, certain residues were removed from the loop ATP-binding cleft with a relocation of critical residues in ex19del, while the position of L858R mutation was in the activation loop (A loop), which was distant from ATP-binding cleft, the substitution of arginine contributed to a steady active conformation (Reguart and Remon 2015; Yun et al. 2007; Wee and Wang 2017). The compaction of the ATP-binding site in L858R mutation was looser than that in ex19del, which might account for the affinities and the sensitivity differences to TKIs (Wee and Wang 2017). Second, mutations could alter the biological behaviors of cancer cells. Ex19del cells produced more G1 phase arrest 7 days after receiving gefitinib, while cells with L858R mutation had greater proportion cells in the G2 phase, which suggested a poor degree of inhibition and a further process of mitosis in L858R cells (Zhu et al. 2008; Hong et al. 2019). The EGFR-TKI inhibition level of downstream signals also varies among mutations, the study showed that downstream effectors of phosphorylated EGFR, including Akt and Erk1/2 signals, are more likely to be inhibited by gefitinib in ex19del cells than in L858R cells, which might be associated with the differential sensitivity to EGFR-TKIs (Zhu et al. 2008; Nagano et al. 2018; Sordella et al. 2004; Paez et al. 2004). Besides, L858R mutation could raise cell invasive ability with an up-regulated CXCR4 through CXCL12-CXCR4 pathway, and facilitate the formation of malignant pleural effusion (Tsai et al. 2015). Thirdly, patients with exon 21 mutation are more likely to harbor concomitant mutations compared with ex19del (69% vs. 41%), while the occurrence of concomitant mutations affects prognosis with a significantly reduced objective response rate (ORR) (44% vs. 77%) and survival (median progression-free survival [PFS]: 6.20 months vs. 18.77 months, median OS: 22.70 months vs. not reached) (Hong et al. 2018; Barnet et al. 2017). Fourthly, mechanisms of resistance vary in cells with different mutations, patients with L858R mutations have a higher proportion of unknown resistance mechanisms (32.9% vs. 20.1%) and a lower likelihood of T790M mutation compared with ex19del (36.5% vs. 50.4%), while patients with T790M mutation achieved a better survival than other resistance mechanisms with a median OS of 36.0 months (Ke et al. 2017; Goag et al. 2018). Besides, C797S mutation was a common resistant mechanism to T790M-targeting EGFR-TKIs, which was more frequent in ex19del patients than L858R mutation patients (Wang et al. 2016; Gunther et al. 2016; Thress et al. 2015; Papadimitrakopoulou et al. 2020). Finally, patients with L858R mutation had a higher value of tumor mutation burden (TMB) than patients with ex19del, while TMB was a negative prognostic factor of clinical outcomes for EGFR-mutant NSCLC patients receiving EGFR-TKI (Jiao et al. 2019). Therefore, ex19del and L858R mutation subgroups have specific mechanisms, which accounts for different efficacies to treatments.

Distinct treatments for sensitive EGFR subtypes

Since both ex19del and L858R mutation subtypes were sensitive to EGFR-TKIs, clinical trials explored the therapeutic efficacy of targeted therapy including monotherapy and combined therapy for advanced EGFR-mutant NSCLC patients, the difference of efficacy between EGFR mutation subtypes was estimated in subgroup analyses. Data was summarized in Fig. 1, Fig. 2 and Table 1.

Fig. 1.

Fig. 1

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PFS benefits for patients with EGFR ex19del or exon 21 L858R mutation in clinical trials

Fig. 2.

Fig. 2

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OS benefits for patients with EGFR ex19del or exon 21 L858R mutation in clinical trials

Table 1.

Summarization of clinical trials

Trial Intervention arm Control arm subgroup PFS OS Citation
Median HR P Median HR P
IPASS Gefitinib Carboplatin + paclitaxel All 9.5 vs 6.3 0.48 (0.36–0.64)  < 0.001 21.6 vs 21.9 1.00 (0.76–1.33) 0.99 Mok et al. 2009; Fukuoka et al. 2011)
L858R 0.55 (0.35–0.87) / / / /
ex19del 0.38 (0.26–0.56) / / / /
JTO 2017 Gefitinib / All 9.1 / / 18.2 / / Sutiman et al. 2017)
L858R 8.3 / / 16.4 / /
ex19del 10.9 / / 19.9 / /
EURTAC Erlotinib Cisplatin/carboplatin + docetaxel/gemcitabine All 9.7 vs 5.2 0.37 (0.25–0.54)  < 0.0001 22.9 vs 22.1 / 0.97 Rosell et al. 2012; Karachaliou, et al. 2015)
L858R 8.4 vs 6.0 0.55 (0.29–1.02) 0.0539 17.7 vs NA 0.99 (0.56–1.76) /
ex19del 11.0 vs 4.6 0.30 (0.18–0.50)  < 0.0001 25.0 vs NA 0.94 (0.57–1.54) /
CONVINCE Icotinib Cisplatin + pemetrexed All 11.2 vs 7.9 0.61 (0.43–0.87) 0.006 30.5 vs 32.1 / 0.885 Shi et al. 2017)
L858R 11.1 vs 7.8 0.76 (0.43–1.33) 0.331 29.1 vs 26.7 / 0.526
ex19del 11.2 vs 8.0 0.66 (0.38–1.14) 0.136 32.3 vs 38.8 / 0.407
INCREASE Icotinib-HD Icotinib L858R 12.9 vs 9.2 0.75 (0.53–1.05)  < 0.05 / / / Li et al. 2020)
Icotinib / ex19del vs L858R 12.5 vs 9.2 0.80 (0.57–1.13) 0.11 / / /
LUX-Lung3 Afatinib Cisplatin + pemetrexed All 11.1 vs 6.9 0.58 (0.43–0.78) 0.001 28.2 vs 28.2 0.88 (0.66–1.17) 0.39 Sequist et al. 2013; Yang et al. 2015)
L858R / 0.73 (0.46–1.17) 0.01 27.6 vs 40.3 1.30 (0.80–2.11) 0.29
ex19del / 0.28 (0.18–0.44) 0.01 33.3 vs 21.1 0.54 (0.36–0.79) 0.0015
LUX-Lung6 Afatinib Gemcitabine + pemetrexed All 11.0 vs 5.6 0.28 (0.20–0.39)  < 0.0001 23.1 vs 23.5 0.93 (0.72–1.22) 0.61 Wu et al. 2014; Yang et al. 2015)
L858R / 0.32 (0.19–0.52) / 19.6 vs 24.3 1.22 (0.81–1.83) 0.34
ex19del / 0.20 (0.13–0.33) / 31.4 vs 18.4 0.64 (0.44–0.94) 0.023
LUX-Lung7 Afatinib Gefitinib All 11.0 vs 10.9 0.73 (0.57–0.95) 0.017 27.9 vs 24.5 0.86 (0.66–1.12) 0.258 Park et al. 2016; Paz-Ares et al. 2017)
L858R 10.9 vs 10.8 0.71 (0.48–1.06) / 25.0 vs 21.2 0.91 (0.62–1.36) 0.6585
ex19del 12.7 vs 11.0 0.76 (0.55–1.06) / 30.7 vs 26.4 0.83 (0.58–1.17) 0.2841
ARCHER1050 Dacomitinib Gefitinib All 14.7 vs 9.2 0.59 (0.47–0.74)  < 0.0001 41.0 vs 33.6 0.75 (0.59–0.95) 0.0155 Wu et al. 2017; Mok et al. 2018)
L858R 12.3 vs 9.8 0.63 (0.44–0.88) 0.0068 32.5 vs 23.2 0.67 (0.47–0.94) 0.0203
ex19del 16.5 vs 9.2 0.55 (0.41–0.75)  < 0.0001 36.7 vs 30.8 0.85 (0.62–1.15) 0.3021
FLAURA Osimertinib Gefitinib/erlotinib All 18.9 vs 10.2 0.46 (0.37–0.57)  < 0.001 38.6 vs 31.8 0.80 (0.64–1.00) 0.0462 Ramalingam et al. 2020; Soria et al. 2018)
L858R 14.4 vs 9.5 0.51 (0.36–0.71)  < 0.001 / 1.00 (0.71–1.40) /
ex19del 21.4 vs 11.0 0.43 (0.32–0.56)  < 0.001 / 0.68 (0.51–0.90) /
JMIT Gefitinib + pemetrexed Gefitinib All 15.8 vs 10.9 0.69 (0.49–0.96) 0.028 / / / Cheng et al. 2016)
L858R 12.6 vs 10.9 0.58 (0.33–1.01) 0.054 / / /
ex19del 17.1 vs 11.1 0.67 (0.43–1.05) 0.078 / / /
NCT02148380 Gefitinib + pemetrexed + carboplatin Gefitinib All 17.5 vs 11.9 0.48 (0.29–0.78) 0.003 32.6 vs 25.8 0.36 (0.20–0.67) 0.001 Han et al. 2017)
L858R / 0.31 (0.15–0.66) / / / /
ex19del / 0.60 (0.30–1.21) / / / /
NEJ009 Gefitinib + carboplatin + pemetrexed Gefitinib All 20.93 vs 11.17 0.49 (0.39–0.62)  < 0.001 50.90 vs 38.80 0.72 (0.55–0.95) 0.021 Hosomi et al. 2020)
L858R / 0.55 (0.38–0.80) / / 0.80 (0.53–1.20) /
ex19del / 0.47 (0.34–0.64) / / 0.65 (0.44–0.97) /
CTONG1509 Erlotinib + bevacizumab Erlotinib All 18.0 vs 11.3 0.55 (0.41–0.75)  < 0.001 / / / Zhou et al. 2019)
L858R 19.5 vs 9.7 0.51 (0.33–0.79)  < 0.001 / / /
ex19del 17.9 vs 12.5 0.62 (0.41–0.92)  < 0.001 / / /
NEJ026 Erlotinib + bevacizumab Erlotinib All 16.9 vs 13.3 0.61 (0.42–0.88) 0.016 / / / Saito et al. 2019)
L858R 17.4 vs 13.7 0.57 (0.33–0.97) / / / /
ex19del 16.6 vs 12.4 0.69 (0.41–1.16) / / / /
JO25567 Erlotinib + bevacizumab Erlotinib All 16.0 vs 9.7 0.54 (0.36–0.79) 0.0015 47.0 vs 47.4 0.81 (0.53–1.23) 0.3267 Seto et al. 2014)
L858R 13.9 vs 7.1 0.67 (0.38–1.18) 0.1653 / / /
ex19del 18.0 vs 10.3 0.41 (0.24–0.72) 0.0011 / / /
RELAY Erlotinib + ramucirumab Erlotinib All 19.4 vs 12.4 0.59 (0.46–0.76)  < 0.0001 / / / Nakagawa et al. 2019)
L858R 19.4 vs 11.2 0.62 (0.44–0.87) 0.006 / / /
ex19del 19.6 vs 12.5 0.65 (0.47–0.90) 0.0098 / / /
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EGFR-TKI is more beneficial for ex19del patients than L858R mutation patients

First-generation EGFR-TKI

Clinical trials demonstrated significant prolonged PFS of targeted therapy by comparing first-generation EGFR-TKIs with chemotherapy in advanced EGFR-mutant NSCLC patients (median PFS: gefitinib vs. chemotherapy [IPASS trial], 9.5 months vs. 6.3 months, P < 0.001; erlotinib vs. chemotherapy [EURTAC trial], 9.7 months vs. 5.2 months, P < 0.0001; icotinib vs. chemotherapy [CONVINCE trial] 11.2 months vs. 7.9 months, P = 0.006), however, no benefit was found in OS analyses (Mok et al. 2009; Fukuoka et al. 2011; Rosell et al. 2012; Shi et al. 2017; Karachaliou et al. 2015).

In subgroup analyses, efficacies varied among different subtypes of mutations. For ex19del patients, significant PFS benefit was found in IPASS trial (HR 0.38, 95% CI 0.26–0.56) and EURTAC trial (HR 0.30, 95% CI 0.18–0.50) when comparing first-generation EGFR-TKIs with chemotherapy. While only IPASS trial showed a significant PFS for L858R mutation patients (HR 0.55, 95% CI 0.35–0.87) (Fukuoka et al. 2011; Rosell et al. 2012). Neither of mutation subgroups showed significant OS benefit (Fukuoka et al. 2011; Rosell et al. 2012; Shi et al. 2017; Karachaliou et al. 2015). Meta-analysis showed that the application of first-generation EGFR-TKIs significantly improved PFS for both ex19del patients (HR 0.28, 95% CI 0.20–0.40) and L858R patients (HR 0.44, 95% CI 0.34–0.57), but had no significant benefit on OS compared with chemotherapy (Kuan et al. 2015). Furthermore, several trials conducted a direct comparison between ex19del and L858R mutation patients. In PFS analysis, Sutiman N et al. found that PFS outcome of ex19del patients was superior to patients with L858R mutation after the administration of gefitinib (median PFS: 8.3 months vs. 10.9 months, P = 0.006) in a previous retrospective, observational cohort study(Sutiman et al. 2017). However, no significant PFS difference in a direct comparison between subgroups was shown in IPASS trial or INCREASE trial (Fukuoka et al. 2011; Li et al. 2020). A meta-analysis also conducted a direct comparison and demonstrated an improved PFS for ex19del patients (HR 0.75, 95% CI 0.65–0.85) over L858R mutation patients (Zhang et al. 2014). Besides, INCREASE study further evaluated the efficacy of high dose icotinib (250 mg, thrice daily) for L858R mutation patients, which demonstrated a prolonged PFS than patients receiving regular dose icotinib (125 mg, thrice daily) (12.9 months vs. 9.2 months, HR 0.75, 95% CI 0.53–1.05, P < 0.05) (Li et al. 2020). It suggested that prognosis could be improved for patients with L858R mutations by increasing the dose of EGFR-TKIs with a manageable toxicity. As for OS analysis, only EURTAC trial found a significant OS benefit in the direct comparison between ex19del patients and L858R mutation patients after the application of erlotinib (median OS: 25.0 months vs. 17.7 months, P = 0.001) (Karachaliou, et al. 2015).

In summary, for first-generation EGFR-TKI, clinical trials demonstrated PFS benefit compared with chemotherapy for both sensitive EGFR mutation subtypes. Subgroup analyses revealed a tendency of more potential benefit for ex19del patients than L858R mutation patients.

Second-generation EGFR-TKI

Clinical trials demonstrated the efficacy of irreversible second-generation EGFR-TKI, afatinib in advanced EGFR-mutant NSCLC patients. Significantly prolonged PFS was found when comparing afatinib with chemotherapy (median PFS: LUX-Lung 3 trial, 11.1 months vs. 6.9 months, P = 0.001; LUX-Lung 6 trial, 11.0 months vs. 5.6 months, P < 0.0001) (Sequist et al. 2013; Wu et al. 2014). However, clinical benefit was not presented in OS analyses (Yang et al. 2015). In subgroup analyses, for patients with ex19del, significant prolonged PFS was shown in both studies (LUX-Lung 3 trial, HR 0.28, 95% CI 0.18–0.44; LUX-Lung 6 trial, HR 0.20, 95% CI 0.13–0.33), while only LUX-Lung 6 trial showed significant PFS benefit for patients with L858R mutation (HR 0.32, 95% CI 0.19–0.52) (Sequist et al. 2013; Wu et al. 2014). In OS analyses, patients with ex19del also achieved significant survival benefit (LUX-Lung 3 trial, HR 0.54, 95% CI 0.36–0.79; LUX-Lung 6 trial, HR 0.64, 95% CI 0.44–0.94), while no OS benefit for L858R mutation patients (Yang et al. 2015). Meta-analysis showed both significant PFS (HR 0.24, 95% CI 0.17–0.33) and OS (0.59, 95% CI 0.47–0.73) benefit for patients with ex19del, while no survival benefit for L858R patients was demonstrated when comparing afatinib with chemotherapy (Kuan et al. 2015). The results showed that patients with ex19del had a better tendency of survival compared with L858R mutation patients after administration with afatinib.

Since previous studies had demonstrated better efficacy for EGFR-TKIs than chemotherapy, further explorations on EGFR-TKIs were conducted while setting first-generation EGFR-TKIs (mainly gefitinib or erlotinib) as comparisons. LUX-Lung 7 trial compared afatinib with gefitinib, for sensitive EGFR-mutant NSCLC patients, the survival benefit was found in PFS analysis (median PFS: 11.0 months vs. 10.9 months, P = 0.017), but not in OS analysis. No survival benefit was found in subgroup analyses for patients with ex19del or L858R mutation (Park et al. 2016; Paz-Ares et al. 2017).

Besides, ARCHER 1050 trial demonstrated a significant survival benefit of dacomitinib in both PFS (median PFS, 14.7 months vs. 9.2 months, P < 0.0001) and OS (median OS, 41.0 months vs. 33.6 months, P = 0.0155) analyses for advanced EGFR-mutant patients compared with gefitinib. As for subgroup analyses, survival outcomes differed from afatinib. Patients with L858R mutation achieved both PFS (HR 0.63, 95% CI 0.44–0.88) and OS (HR 0.67, 95% CI 0.47–0.94) benefit, while patients with ex19del only achieved significant PFS benefit (HR 0.55, 95% CI 0.41–0.75) (Wu et al. 2017; Mok et al. 2018). However, the outcomes of OS analysis remained controversial, for ORR did not show a significant result in statistical analysis with a fixed order, besides, OS curves intersected at 12 months which indicated that the potential impact of subsequent treatment effects could not be neglected, thus the credibility of OS results remained questionable. Therefore, although EGFR-mutant patients receiving second-generation EGFR-TKIs showed a survival benefit, subgroup analyses demonstrated more benefit for ex19del patients.

Third-generation EGFR-TKI

As for third-generation EGFR-TKI, significant PFS (median PFS, 18.9 months vs. 10.2 months, P < 0.001) and OS (median OS: 38.6 months vs. 31.8 months, P = 0.0462) benefit was achieved for EGFR-mutant patients receiving osimertinib compared with first-generation EGFR-TKIs. Subgroup analyses showed ex19del patients achieved a significant survival benefit on both PFS (HR 0.43, 95% CI 0.32–0.56) and OS (HR 0.68, 95% CI 0.51–0.90) analyses, while L858R mutation patients only achieved a significant PFS benefit (HR 0.51, 95% CI 0.36–0.71), which indicated a superior benefit for ex19del patients receiving osimertinib (Ramalingam et al. 2020; Soria et al. 2018).

In summary, EGFR-TKI monotherapy could improve the survival of advanced EGFR-mutant NSCLC patients, however subgroup analyses showed distinct survival outcomes. Apart from long-term survival of dacomitinib for L858R mutation patients, ex19del patients could benefit more from monotherapy than patients with L858R mutation. A previous network meta-analysis also suggested that osimertinib was the optimal treatment for ex19del patients considering PFS benefit (Zhao et al. 2019).

The efficacy of combined therapy in subgroups is still controversial

Combination of EGFR-TKI and chemotherapy

Combination therapy further demonstrated clinical benefits compared with EGFR-TKI monotherapy. Several studies explored the clinical efficacy of the combination of EGFR-TKIs and chemotherapy, significant PFS benefit was found in JMIT trial (median PFS: 15.8 months vs 10.9 months, P = 0.028), NCT02148380 trial (median PFS, 17.5 months vs. 11.9 months, P = 0.003) and NEJ009 trial (median PFS, 20.9 months vs. 11.2 months, P < 0.001) when comparing with gefitinib. As for OS analysis, prolonged survival was revealed in both NCT02148380 trial (median OS: 32.6 months vs. 25.8 months, P = 0.001) and NEJ009 trial (median OS: 50.9 months vs. 38.8 months, P = 0.021) (Hosomi et al. 2020; Cheng et al. 2016; Han et al. 2017).

In subgroup analyses, a superior benefit on PFS was demonstrated for L858R patients receiving combination therapy than patients receiving gefitinib in NCT02148380 trial (HR 0.31, 95% CI 0.15–0.66) and NEJ009 trial (HR 0.55, 95% CI 0.38–0.80). NEJ009 trial also showed significant PFS benefit for ex19del patients (HR 0.47, 95% CI 0.34–0.64)(Hosomi et al. 2020; Cheng et al. 2016; Han et al. 2017). A previous network meta-analysis demonstrated treatment efficacy of the combination of gefitinib and chemotherapy for L858R mutation patients in terms of PFS (Zhao et al. 2019). In OS analysis, a significant benefit was achieved only for ex19del patients (HR 0.65, 95% CI 0.44–0.97) in NEJ009 trial (Hosomi et al. 2020). Although survival benefit was revealed in combination therapy of EGFR-TKIs and chemotherapy, the prognosis outcomes in EGFR subtypes were controversial and needed to be further verified.

Combination of EGFR-TKI and antiangiogenic therapy

The combination of EGFR-TKI and antiangiogenic drugs also revealed efficacy in first-line treatment for advanced EGFR-mutant NSCLC patients. Three clinical trials explored the prognosis of the combination of erlotinib and bevacizumab compared with erlotinib, including the CTONG1509 trial, NEJ026 trial and JO25567 trial. All of the trials demonstrated significant PFS benefit for the combination of antiangiogenic therapy and EGFR-TKIs (median PFS: CTONG1509 trial, 18.0 months vs. 11.3 months, P < 0.001; NEJ026 trial, 16.9 months vs. 13.3 months, P = 0.016; JO25567 trial, 16.0 months vs. 9.7 months, P = 0.0015) (Zhou et al. 2019; Saito et al. 2019; Seto et al. 2014). OS results of most trials were immature, and no OS benefit was found in JO25567 trial (median OS: 47.0 months vs. 47.4 months, P = 0.3267) (Seto et al. 2014). Besides, phase 3 trial (RELAY) explored the combination of erlotinib and ramucirumab compared with erlotinib alone, where significant prolonged PFS was also found for combined therapy (median PFS: 19.4 months vs. 12.4 months, P < 0.0001) (Nakagawa et al. 2019). In addition, patients receiving the combination of targeted therapy and antiangiogenic therapy had a less frequency of T790M mutation, as well as other complex mutations and amplifications than patients receiving EGFR-TKI monotherapy at the time of disease progression, which might achieve a better efficacy in subsequent therapies(Zeng et al. 2020; Wang et al. 2018). However, it was reported that combined therapy would bring an increased risk of toxicity, which might bring negative effects on patients’ survival outcomes and quality of life (Zhao et al. 2019).

When considering subgroup analyses, significant PFS benefit of combined therapy was found in CTONG1509 trial (HR 0.51, 95% CI 0.33–0.79), NEJ026 trial (HR 0.57, 95% CI 0.33–0.97) and RELAY trial (HR 0.62, 95% CI 0.44–0.87) for L858R mutation patients, while in CTONG1509 trial (HR 0.62, 95% CI 0.41–0.92), JO25567 trial (HR 0.41, 95% CI 0.24–0.72) and RELAY trial (HR 0.65, 95% CI 0.47–0.90) for ex19del patients. In other words, CTONG1509 trial and NEJ026 trial showed the superiority of combined therapy for L858R mutation patients, while JO25567 trial showed a better survival outcome for ex19del patients(Zhou et al. 2019; Saito et al. 2019; Seto et al. 2014). In RELAY trial, patients with L858R mutation had a slight advantage of progression risk (HR 0.62 vs. 0.65) and a slight disadvantage of median PFS (19.4 months vs. 19.6 months) compared with ex19del patients (Nakagawa et al. 2019). Hence, prognostic outcomes of combined targeted and antiangiogenic therapy were controversial and might bring more potential benefits to L858R mutation patients, which was worthy of further study.

Evidence of differences in therapeutic effects from real-world data

In addition to survival outcomes from clinical trials, real-world studies also showed therapeutic distinctions in different subgroups of advanced sensitive EGFR-mutant NSCLC patients. Most studies focused on first-line EGFR-TKI monotherapy. Lau et al. compared second-generation EGFR-TKI (afatinib) with first-generation EGFR-TKIs (gefitinib, erlotinib), results showed significant OS benefit for patients with ex19del (median OS: 48.8 months vs. 26.4 months), while not for L858R mutation patients (median OS: 25.4 months vs. 20.6 months) (Lau et al. 2019). Further studies focused on direct comparisons between EGFR mutation subgroups. Li et al. explored the efficacy of first-line EGFR-TKIs in a real-world setting, results showed ex19del patients achieved numerically increased time to next treatment (TTNT) and OS compared with L858R mutation patients when both administrated with erlotinib (median TTNT: 14.0 months vs. 12.1 months, median OS: 24.6 months vs. 19.9 months) and afatinib (median TTNT: 12.6 months vs. 11.2 months, median OS: 23.0 months vs. 16.2 months) (Li et al. 2019). Ho et al. also demonstrated significantly superior PFS for ex19del patients when comparing with L858R mutation patients after receiving first-line afatinib (16.0 months vs. 8.7 months, P = 0.001) (Ho et al. 2019). Besides, in real-world clinical practice, NCT03370770 trial demonstrated a prolonged OS (median OS: 45.7 months vs. 35.2 months) when comparing ex19del patients with L858R mutation patients for advanced EGFR-mutant NSCLC who received first-line afatinib and sequential osimertinib after the occurrence of T790M mutation (Hochmair et al. 2019, 2018). Thus, evidence from real-world data also supported the therapeutic distinctions of EGFR mutation subtypes.

Conclusions

More and more evidence showed that although both ex19del and L858R mutation were sensitive EGFR mutations, they had specific molecular mechanisms and should be treated as distinct types of NSCLC. Therapeutic effects reflected the difference. In general, first-line EGFR-TKI monotherapy was beneficial for advanced EGFR-mutant NSCLC patients, subgroup analyses showed monotherapy, especially osimertinib, might be more beneficial for patients with ex19del. Besides, combined therapy was superior to first-generation EGFR-TKI for EGFR-mutant patients, subgroup analyses showed controversial outcomes, generally combination was beneficial for patients with L858R mutation, especially when combining EGFR-TKI with antiangiogenic drugs.

Prospectively, since ex19del and L858R mutation are distinct types of NSCLC, clinicians should administrate optimal treatments for patients with different types of mutations separately. However, current results are still controversial, for instance, both dacomitinib and combined therapy could bring a survival benefit for L858R mutation patients, which is worthy of further comparison. Besides, patients with L858R mutation had a higher TMB value than ex19del patients, the previous retrospective study also demonstrated the efficacy of immune checkpoint blockade treatment for patients with L858R mutation, which was similar to EGFR wild-type patients and better than ex19del patients, thus immunotherapy might be a potential treatment option for L858R mutation patients (Offin et al. 2019; Hastings et al. 2019). Furthermore, our study mainly focused on first-line treatments for patients with advanced EGFR-mutated NSCLC, while current evidence showed that patients with localized diseases could also benefit from EGFR-TKIs (Marquez-Medina and Popat 2016). Retrospective study showed a superior post-recurrence survival (PRS) for ex19del patients compared with L858R mutation patients (median PRS: 27.0 months vs. 21.2 months, P = 0.016), suggesting directions for further researches (Zhang et al. 2018). With the development of next-generation sequencing (NGS), studies on mutation subtypes and correlative mutations will provide a reference for further exploration and the best treatment options for patients with different EGFR mutation subtypes.

Acknowledgements

This work was supported by Nation Key Research and Development Program of China (Grant No. 2016YFC1303800).

Author contributions

The manuscript has been read and approved by all the authors.

Funding

This work was supported by Nation Key Research and Development Program of China (Grant No. 2016YFC1303800).

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflict of interest.

Footnotes

Publisher's Note

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