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Background:
Systematic Review

Resistance Mutation Profiles Associated with Current Treatments for Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer in the United States: A Systematic Literature Review

by
Pratyusha Vadagam
1,*,
Dexter Waters
1,
Anil Bhagat
2,
Yuting Kuang
2,
Jennifer Uyei
2 and
Julie Vanderpoel
1
1
Johnson & Johnson, 800 Ridgeview Dr, Horsham, PA 19044, USA
2
IQVIA Inc., 1850 Gateway Drive, San Mateo, CA 94404, USA
*
Author to whom correspondence should be addressed.
Curr. Oncol. 2025, 32(4), 191; https://doi.org/10.3390/curroncol32040191
Submission received: 19 December 2024 / Revised: 8 March 2025 / Accepted: 24 March 2025 / Published: 25 March 2025
(This article belongs to the Section Thoracic Oncology)
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Abstract

:
Treatment resistance due to gene alterations remains a challenge for patients with EGFR-mutated advanced or metastatic non-small-cell lung cancer (a/mNSCLC). A systematic literature review (SLR) was conducted to describe resistance mutation profiles and their impact on clinical outcomes in adults with a/mNSCLC in the United States (US). A comprehensive search of MEDLINE and Embase (2018–August 2022) identified 2986 records. Among 45 included studies, osimertinib was the most commonly reported treatment (osimertinib alone: 15 studies; as one of the treatment options: 18 studies), followed by other tyrosine kinase inhibitors (TKIs; 5 studies) and non-TKIs (1 study). For first-line (1L) and second-line (2L) osimertinib, the most frequent EGFR-dependent resistance mechanisms were T790M loss (1L: 15.4%; 2L: 20.5–49%) and C797X mutation (1L: 2.9–12.5%; 2L: 1.4–22%). EGFR-independent mechanisms included MET amplification (1L: 0.6–66%; 2L: 7.2–19%), TP53 mutation (1L: 29.2–33.3%), and CCNE1 amplification (1L: 7.9%; 2L: 10.3%). For patients receiving osimertinib, EGFR T790M mutation loss, EGFR/MET/HER2 amplification, RET fusion, and PIK3CA mutation were associated with worse progression-free survival. Resistance mechanisms resulting from current NSCLC treatments in the US are complex, underscoring the need to address such heterogeneous resistance profiles and improve outcomes for patients with EGFR-mutated a/mNSCLC.

1. Introduction

Lung cancer is the most common cause of cancer death in the United States (US) with an estimated 238,340 new cases and 127,070 deaths in 2023 [1]. Non-small-cell lung cancer (NSCLC) is the most common sub-type of lung cancer, accounting for approximately 80–85% of all cases [2]. Widespread screening has the potential to diagnose earlier-stage cancers; however, more than half of newly diagnosed patients with lung cancer have advanced or metastatic disease [3]. One of the most common oncogenic drivers in NSCLC is mutation in the epidermal growth factor receptor (EGFR). In a cohort of patients with recurrent or metastatic lung adenocarcinoma, EGFR alterations occurred in up to 28% of patients, although its prevalence could be largely impacted by factors such as age, sex, race, and smoking status [4].
Molecular testing in NSCLC is now considered standard of care, and genome-sequencing approaches have led to the discovery of a growing number of oncogenic mutations [5]. The majority of the oncogenic drivers in NSCLC represent somatic events that result in the hyperactivation of a kinase and oncogene addiction in the tumor cells. Therefore, targeted therapies have a significantly larger therapeutic window than traditional cytotoxic chemotherapy [6]. Studies have demonstrated clinical efficacy with second- and third-generation tyrosine kinase inhibitors (TKIs) [7,8,9]. Most recently, osimertinib has been found to have overall survival (OS) benefit over first-generation EGFR targeting TKIs and is associated with a favorable tolerability profile, positioning it as a standard first-line treatment option for common sensitizing EGFR mutations including exon 19 deletion and exon 21 L858R (L858R) [10].
Considering the development of targeted therapies, the National Comprehensive Cancer Network (NCCN) recommends that all patients with metastatic non-squamous NSCLC undergo biomarker testing for oncogenic drivers including ALK rearrangements, BRAF mutations, EGFR mutations, HER2 mutations, and ROS1 rearrangement. However, mutations can emerge during treatment and trigger acquired resistance to targeted therapy, but such acquired mutations have not been commonly assessed among patients with disease progression and remain to be further characterized.
Several mechanisms capable of triggering acquired resistance have been described in patients with EGFR-mutated advanced NSCLC, such as EGFR T790M mutation, EGFR C797S mutations, MET amplification, and small-cell transformation. These mechanisms, which may be EGFR-dependent or EGFR-independent, are often associated with poor prognoses, including shorter progression-free survival (PFS). In EGFR-dependent resistance mechanisms, tumor cell proliferation depends largely on EGFR signaling. On the other hand, EGFR-independent resistance mechanisms are characterized by the predominance of other parallel pathways that bypass EGFR signaling.
Despite the emerging targeted therapies in treating EGFR-mutated NSCLC, treatment resistance remains a challenge for a subset of patients due to several factors, including reduced sensitivity to TKIs and the presence of concurrent genetic alterations, such as MET amplifications or modifiers of response to TKIs [10]. Post-osimertinib, pharmacological options become limited, with chemotherapy remaining the main therapeutic strategy [11]. In view of this, a comprehensive understanding of the current landscape of resistance mechanisms for EGFR-mutated NSCLC is needed to allow for the identification of unmet medical needs. A systematic literature review (SLR) was conducted to describe the resistance mutation profiles and impact of resistance mutations on clinical outcomes in adults with locally advanced or metastatic NSCLC (a/mNSCLC) with EGFR mutation. Considering potential geographical differences in population characteristics, treatment landscape, and healthcare settings, this review focused on studies involving patients in the US.

2. Materials and Methods

An SLR was conducted following the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions [12] and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [13]. A detailed protocol was developed prior to conducting the review and was registered prospectively in PROSPERO (registration ID CRD 42022355822).
A comprehensive search was performed in MEDLINE® Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Medline® Daily, Medline and Versions®, and EMBASE by using the OvidSP® platform to identify relevant studies. The databases were searched from 2018 to 3 August 2022 and limited to English language publications (complete search strategies are presented in Supplementary Table S1). Since osimertinib was approved by the Food and Drug Administration in 2018 for the first-line treatment of metastatic NSCLC with EGFR mutation, only evidence from 2018 onwards was included to reflect the resistance mutation profiles associated with the more recent treatment landscape. In addition to the bibliographic databases, websites of the following selected conferences for the most recent meetings were searched: American Society of Clinical Oncology (ASCO) Annual Meeting, European Society for Medical Oncology (ESMO) Congress, World Conference on Lung Cancer (WCLC), International Society for Pharmacoeconomics and Outcomes Research (ISPOR) conference, and Academy of Managed Care Pharmacy (AMCP) Annual Meeting. The bibliographies of recently published reviews on the related topic area were also reviewed to help mitigate the risk of publication bias and to identify as much relevant evidence as possible [12].
Studies were eligible for inclusion if they included adults (18 years or older) with EGFR-mutated a/mNSCLC. There were no restrictions for interventions or comparators. Clinical trials, observational studies, and genome-sequencing studies that were published between 2018 and 3 August 2022 were included. For geography, only studies conducted in the US or those including at least a proportion of patients from the US were included. Case reports and review articles were excluded, and so were studies that did not include patients in the US and studies that did not include human subjects.
Two reviewers working independently reviewed the title and abstract of all unique studies identified by the search. Records were excluded if they did not meet pre-defined inclusion criteria as assessed by both reviewers; records were retained for full-text review if assessed as definitely or possibly relevant by both reviewers. Further, two reviewers working independently assessed each full-text publication to determine eligibility, and reasons for exclusion were documented. At any stage, records for which there was uncertainty about inclusion/exclusion or there was a discrepancy between the two reviewers, a third reviewer adjudicated a decision to include or exclude. The process of search and screening was summarized in a PRISMA flow diagram. Data extraction was conducted by two independent reviewers and discrepancies were checked against the source document by a third reviewer. Publications reporting results for the same study were grouped per study.
Key data on methodological characteristics, selection criteria, study population/patient characteristics, and results were extracted from the included studies. Number and proportion of patients with different mechanisms of resistance mutation and co-mutations were extracted. Key outcomes of interest were resistance mutation profile (mechanisms of acquired resistance, especially to EGFR tyrosine kinase inhibitors [EGFR TKIs]) and the impact of resistance mutation on clinical outcomes (OS, PFS, overall response rate [ORR], complete response [CR], partial response [PR], duration of response, time to next treatment, and time to treatment discontinuation [TTD]). Acquired resistance mechanisms and alterations were recorded as defined by the study authors and not limited to paired samples of the same testing modality.
Risk of bias for the included non-randomized and randomized studies was assessed according to the Newcastle-Ottawa scale (NOS) [14] and Cochrane Risk of Bias Tool (RoB2) [15], respectively.

3. Results

3.1. Study Selection

The search and screening results are illustrated in the PRISMA flow diagram in Figure 1. A total of 3023 publications were identified through database searches. After de-duplication, 2986 unique records were retained for title and abstract review. A total of 121 records were retained for full-text review, and 8 additional records meeting the eligibility criteria were identified from manual searches of conferences and bibliographies of review articles. After full-text review, 63 eligible publications reporting data on 45 unique studies were included for data extraction.

3.2. Study and Patient Characteristics

Study and patient characteristics are summarized in Table 1, with additional information in Supplementary Table S2. The majority of the included studies were observational studies (77.8%, n = 35) [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50], and the rest were single-arm trials (8.9%, n = 4) [51,52,53,54], non-randomized clinical trials (8.9%, n = 4) [55,56,57,58], or randomized clinical trials (RCTs) (4.4%, n = 2) [8,59]. Twenty-three (51.1%) studies were published as journal articles, and twenty-two (48.9%) were published as conference abstracts. Twenty-seven studies (60%) included US-only populations, and eighteen (40%) studies included a mix of US populations and other geographies/countries. Fifteen studies reported on osimertinib alone, and eighteen included osimertinib as one treatment option among patients treated with TKIs or non-TKI treatment. Six studies reported on treatments other than osimertinib, of which five reported on TKIs including poziotinib, rociletinib, aumolertinib, capmatinib, and erlotinib and one reported on non-TKIs. Treatment type was not specified in six studies.
The majority of studies (64%) reported on the line of therapy (LoT). A total of 6 studies investigated first-line therapy alone, 18 studies investigated first-line therapy and beyond, 1 study reported second-line therapy alone and 4 studies reported second-line therapy and beyond. The line of therapy was not specified in 16 studies. The proportion of males ranged from 25% to 85.5% among the included studies. Where reported, the median age ranged from 59 years to 69.5 years. The study period varied across studies and ranged from 2005 to 2022, with a few studies ongoing beyond 2022. The sample size ranged from 9 to 16,715.

3.3. Quality Assessment of Included Studies

The two RCTs were deemed as having some concern for risk of bias due to missing outcome data in the individual studies (see Supplementary Figure S1). Of the 29 studies that did not report clinical outcomes, out of a maximum of 4 stars, the total NOS score was 3 for most studies, suggesting a low risk of bias. A total of 6 studies had 1 star (high risk of bias), 7 studies had 2 stars (medium risk of bias), 13 studies had 3 stars (low risk of bias), and 3 studies had 4 stars (low risk of bias).
Of the 14 observational studies that reported clinical outcomes, out of a maximum of 6 stars, the total NOS score was 2 or 3 stars for most studies, suggesting a medium risk of bias. Two studies had 1 star (high risk of bias), five studies had 2 stars (high risk of bias), five studies had 3 stars (medium risk of bias), and one study each had 4 or 5 stars (low risk of bias) (see Supplementary Table S3).

3.4. Outcomes

3.4.1. Acquired Resistance Mutation Profile by Line of Therapy

  • First-Line osimertinib
Eight studies [8,18,37,39,40,42,54,58] reported the proportion of acquired EGFR-dependent and EGFR-independent resistance mechanisms in patients who received first-line osimertinib. As shown in Figure 2, the resistance mutation profile of patients who received first-line osimertinib was heterogenous and complex. Among the EGFR-dependent mechanisms, T790M loss (15.4%) was the most frequently occurring alteration [18], followed by C797X mutation (2.9–12.5%) [8,37,39,54] and acquired EGFR mutations (11.6%; type unspecified) [18]. Notably, T790M loss was reported as a common molecular alteration at the time of progression to first-line osimertinib [18]. Other mechanisms that occurred less frequently included EGFR amplification (2.9–8.4%) [18,37], L718Q/V mutation (2.9–3.1%) [37], acquired G724S (2.9%) [37], and pocket volume reducing mutation (0.02%) [40]. When osimertinib was given as first-line treatment, no evidence for acquired T790M mutation was detected at resistance (0%) [8,54].
Among the EGFR-independent mechanisms, the most commonly occurring one was MET amplification (0.6–66%) [8,18,37,39,54,58], followed by TP53 mutation (29.2–33.3%) [18,58], CCNE1 amplification (7.9%) [39], HER2 amplification (6.2%) [18], BRAF mutation (2.9–6.0%) [18,37], HER2 exon 20 insertion (5.3%) [54], JAK2 V617F mutation (5.3%) [54], MEK1 mutation (5.3%) [54], KRAS mutation (4.8–5.3%) [18,54], and PIK3CA mutation (3.4–5.3%) [18,54].
Overall, the proportion of patients who experienced co-occurring acquired resistance mechanisms varied from 2.0% to 40.8% (Supplementary Table S4). The proportion of patients who experienced other resistance mechanisms, including cell transformation, were reported to range from 2.9% to 14%, where histologic transformation could potentially be another predominant mechanism of resistance with frequency comparable to other common EGFR-dependent mechanisms. Additional details and information on these mechanisms can be found in Supplementary Table S4.
  • Second-Line osimertinib
Five studies [24,33,39,58,59] reported the proportion of acquired EGFR-dependent and EGFR-independent resistance mechanisms in patients who received second-line osimertinib. The proportion and range of patients who presented with individual resistance mechanisms are presented in Figure 3, with additional details and co-occurring mutations presented in Supplementary Table S5.
Similar to the resistance mutation profile for patients who received first-line osimertinib, T790M loss (20.5–49%) [24,33,59] was the most frequently occurring EGFR-dependent mechanism, followed by C797X mutation (1.4–22%) [33,39,59] and EGFR sensitizing mutation loss (10.3%) [24]. In this setting, among patients who had T790M-positive disease following first-line therapy, the status of T790M mutation was evaluated at the time of resistance to second-line osimertinib. While two studies reported the observation of T790M loss without further characterization [24,59], in one study, the loss of T790M mutation was reported to mediate the acquired resistance to second-line osimertinib and associate with competing mechanisms [33]. Interestingly, acquired C797S mutation was only observed in patients who maintained T790M in one study, where the results were stratified by T790M status [33].
The most commonly occurring EGFR-independent mechanisms among patients who received second-line osimertinib were similar to those reported in patients who received first-line osimertinib. The most commonly occurring mechanism was MET amplification (7.2–19%) [33,39,59], followed by CCNE1 amplification (10.3%) [39]. The proportion of patients with other mechanisms, including cell transformation, was 16.7% [58] (see Supplementary Table S5).
  • Resistance mutation profile for patients who received other lines of osimertinib
Several studies reported resistance mechanisms for other lines of osimertinib. Six studies [17,27,34,36,42,58] reported the proportion of acquired EGFR-dependent and EGFR-independent resistance mechanisms in patients who received first-line osimertinib and beyond—defined as osimertinib as first-line treatment or after prior treatment—and five studies [29,33,42,50,55] reported the proportions in patients who received second-line osimertinib and beyond (Supplementary Tables S6 and S7).
The most frequently occurring EGFR-dependent mechanisms were T790M loss (first-line and beyond: 23.9–50% [17,27,34,42]; second-line and beyond: 30.9–68.3% [33,42,50]) and C797X (first-line and beyond: 11.1–32.0% [17,27,34,36]; second-line and beyond: 11–22.0% [29,33,50]). Notably, the reporting of T790M loss varied across studies. The loss of T790M mutation was reported as a resistance mechanism in two studies [34,42], as an alteration observed at osimertinib progression in two studies [17,50], and as a mediator of acquired resistance in two studies, where the mutation profile was further stratified by T790M status [27,33]. When stratified, the mutation profile for T790M-loss cases were reported to be more diverse and involving EGFR-independent mechanisms, while for T790M-preserved cases, EGFR tertiary mutations were more commonly observed [27,33]. EGFR C797X mutation [27,33] and L792H mutation [27] were considered previously defined osimertinib-resistant EGFR mutations by the study authors and were observed exclusively in T790M-preserved cases.
MET amplification (10.0–23.0%) [17,27,34,36] was reported to be the most frequently occurring EGFR-independent mechanism in patients who received first-line osimertinib and beyond. When stratified by T790M status at resistance, MET amplification was observed in 26.3% of T790M-preserved cases and 4.8% of T790M-loss cases [27]. Among patients who received osimertinib in the second-line therapy and beyond setting, PI3K-AKT-mTOR signaling activating mutation (9.8–12.6%) [33,50] was most frequently occurring, followed by MET amplification (5.5–9.8%) [29,33,50]. When further stratified by T790M status at resistance, PIK3CA mutation was observed in 15.4% of T790M-preserved cases and 7.1% of T790M-loss cases, while MET amplification was observed in 0% of T790M-preserved cases and 14.3% of T790M-loss cases in this setting [33]. Additionally, eight studies that included patients who received an unspecified line of osimertinib reported trends similar to those reported in patients who received first-line osimertinib.
  • Resistance mutation profile for patients who received other treatments
Several studies reported on the proportion of EGFR-dependent and EGFR-independent mechanisms for different combinations of treatments. Eighteen studies [8,16,21,30,31,32,35,36,40,41,43,48,57,58,59] included patients who received TKIs or non-TKIs (including chemotherapy and immunotherapy) where osimertinib was one of the treatment options, six studies [23,51,52,53,55,56] included patients who received other TKIs or non-TKIs, and another six studies [19,20,26,28,38,45] included patients for whom the treatment type was not specified (Supplementary Tables S8–S10).
The most frequently occurring EGFR-dependent mechanisms reported in these studies differed from what was reported for patients who received first-line or second-line osimertinib. For patients who received TKIs or non-TKIs where osimertinib was one of the treatment options, C797X mutation (6.9–79.3%) [21,57] and T790M mutation (32–72%) [32,35] were the most frequently occurring EGFR-dependent mechanisms.
Beyond treatments involving osimertinib, other TKI and non-TKI therapies have also been associated with various resistance mechanisms. For patients who received other TKIs and non-TKIs, T790M mutation (13–90.8%) [35,51] was the most frequently occurring EGFR-dependent mechanism followed by C797X (4.6–16.7%) [23,52]. One study [23] also reported that EGFR alteration was observed in 36% of patients, but the type of alteration was not specified. Similar to patients who received other TKIs and non-TKIs, T790M mutation (0.9–76%) [35,38] was the most frequently occurring EGFR-dependent mechanism in patients who received unspecified treatments. One study reported EGFR mutation in 4.0–19.1% [19] of patients who received unspecified treatments, but the specific type of mutation was not reported.
EGFR-independent mechanisms varied across treatment categories. For patients who received TKIs or non-TKIs where osimertinib was one of the treatment options, the most frequently occurring EGFR-independent mechanisms were PIK3CA alteration (8.9–44.4%) [30,31], RB1 alteration (33.3%) [31], FGFR3 fusion (0.7–33.3%) [30,43], and ALK fusion (0.2–25%) [30,43], while TP53 alteration (45%) [23] and RET fusion (29–71%) [47] were the most frequently occurring mechanisms in patients who received other TKIs/non-TKIs or unspecified treatment, respectively.
Specifically, five studies that exclusively evaluated patients receiving treatments other than osimertinib reported results and revealed complex resistance mutation profiles. Helman et al. [23] observed multiple resistance mechanisms among patients treated with rociletinib in the TIGER-X and TIGER-2 studies, including C797S mutations (4.6%), KRAS/NRAS/HRAS mutations (14%), an NTRK1 fusion (2%), and MET amplification (7.6%). The APOLLO study [52] identified C797S mutations in 16.7% of patients treated with aumolertinib. A phase 2 study [51] of poziotinib reported that 47.8% of patients had EGFR-independent resistance mechanisms and 17.4% had EGFR-dependent resistance mechanisms, including acquired EGFR gatekeeper mutations (13%). Interestingly, C797S mutation was not observed as a resistance mechanism in this study. A phase 1/2 study [53] of capmatinib in combination with erlotinib in patients with MET-positive NSCLC observed acquired T790M mutations in 8.3% of patients. Among patients who had progressed on osimertinib and had been treated with a combination of amivantamab and lazertinib in the CHRYSALIS study [55], 22.2% had non-EGFR/MET mechanisms of osimertinib resistance, and none of these patients responded to treatment. Additionally, 40% were observed to have unknown mechanisms of resistance.

3.4.2. Impact of Acquired Resistance on Clinical Outcomes

Fourteen studies reported clinical outcomes for patients with different types of treatment and acquired resistance mechanisms: response (nine studies) [16,20,23,40,43,46,53,55,56], PFS (eight studies) [18,20,23,26,33,40,47,55], TTD (two studies) [32,33], and OS (one study) [32]. Four studies evaluated the impact of acquired resistance mechanisms on clinical outcomes statistically (Supplementary Table S11). Among these four studies, two reported on osimertinib [18,33], and two reported on other EGFR TKIs or chemotherapy [20,40].
In one study of patients who received osimertinib for acquired EGFR T790M resistance mutation to a prior EGFR TKI, the loss of T790M compared with maintained T790M was associated with worse PFS (median of 4.2 vs. 9.5 months, p = 0.001) and shorter TTD (6.1 months vs. 15.2 months, p = 0.01) [33]. In this study, loss of the T790M mutation was associated with early resistance to osimertinib. In another study that evaluated first-line osimertinib, EGFR amplification, MET amplification, RET fusion, HER2 amplification, and PIK3CA mutation were associated with worse PFS (the median PFS ranged between 4.63 and 15.1 months across subgroups of patients with or without these resistance alterations) [18]. The presence of TP53 mutations and the loss of EGFR T790M were the most common molecular alterations at the time of progression. While TP53 mutation did not have an impact on PFS in the overall population, among patients with CNS metastases, those with TP53 mutations at progression had a worse PFS compared with those without TP53 mutations (median of 11.0 vs. 24.9 months) [33]. Interestingly, longer PFS was observed in patients with EGFR T790M loss (median of 28.1 months vs. 13.2 months) [33], but no further interpretation was provided by the authors.
For other treatments, the presence of acquired EGFR T790M mutation was associated with improved PFS on first-line TKI treatment or chemotherapy. Based on these findings, the authors suggested that tumors expressing the T790M resistance mutation have a more indolent progression of disease than their T790M-negative counterparts [20]. Additionally, no associations were observed between acquired EGFR T790M mutation and TTD or OS on first-line EGFR TKI treatment [40].

4. Discussion

The studies identified in our SLR show that mechanisms of resistance to current NSCLC treatments, primarily osimertinib, in US populations are heterogenous and complex and pose a challenge for treating patients with EGFR-mutated a/mNSCLC. Various mechanisms of resistance were reported in the studies, yet across different lines of osimertinib, T790M loss or C797X mutation was consistently the most frequently reported EGFR-dependent mechanism. Specifically, across studies that reported on resistance to first-line or second-line osimertinib, up to 49% and 22% of patients had T790M loss and C797X, respectively. These estimates are similar to the estimates previously reported by Kobayashi et al. [78]. In a pooled analysis, Kobayashi et al. reported that the incidence of T790M loss after osimertinib treatment in patients with histologically confirmed NSCLC was 58.4% and the incidence of C797S mutation in patients who developed acquired resistance to osimertinib was 21.58%.
Two studies included in the review reported inconsistent results in terms of the clinical impact of T790M loss. Oxnard et al. [33] reported that loss of EGFR T790M mutation was associated with worse PFS and early resistance on second-line osimertinib or beyond. In contrast, Cardona et al. [18] reported that longer PFS was observed in patients with EGFR T790M loss on first-line osimertinib. It is important to note that there are likely biological differences when addressing the T790M mutation in first-line therapy vs. the T790M mutation that develops after using another EGFR TKI. The characterization for T790M loss varied across studies (as resistance mechanism, alteration at progression, or mediator of resistance); nevertheless, the loss of T790M mutation was commonly observed in patients who developed resistance to osimertinib and could be associated with the emergence of different resistance mutation profiles compared with cases with T790M maintained.
In addition, several other EGFR-dependent mechanisms of resistance, including EGFR amplification, mutations in L718Q/V, and G724S, were reported in varying proportions for patients who received first- or second-line osimertinib. Several studies also reported the proportion of patients with EGFR exon 19 deletion, L858R, driver single-nucleotide variant, and exon 20 insertion as part of the mutation profile at progression, without clearly distinguishing EGFR activation mutations and resistance mutations in the report [19,30,53]. Considering that these are typically recognized as EGFR activation mutations, they were not captured as resistance mechanisms.
A variety of EGFR-independent mechanisms were reported across different lines of osimertinib. MET amplification was consistently the most prevalent EGFR-independent mechanism across studies that reported first-line osimertinib only, first-line therapy and beyond, or second-line therapy only, with an observed proportion ranging between 0.6% and 23.0%. This finding is comparable to a pooled analysis published by Kobayashi et al. [78], which reported that 10.65% of patients with NSCLC who progressed on osimertinib had MET amplification. One study in the present review reported a high incidence of 66% for MET amplification among patients receiving first-line osimertinib [58]. While the authors did not provide further interpretation for this high incidence, this observation could be an outlier due to small sample size (n = 9) and other potential bias in sample selection. Other EGFR-independent mechanisms that were reported include CCNE1 amplification, HER2 amplification, RET fusion, and mutations in TP53, BRAF, PIK3CA, and KRAS, among several others. In one study, the authors reported that MET amplification, RET fusion, HER2 amplification, and PIK3CA mutation were associated with worse PFS in patients on first-line osimertinib [18].
Overall, the resistance mechanisms developed during osimertinib treatment are complex, involving both EGFR-dependent and EGFR-independent pathways. Common EGFR-dependent mechanisms observed in the reviewed studies include T790M loss, C797X mutation, EGFR amplification, and mutations in L718Q/V and G724S. Common EGFR-independent mechanisms include MET amplification, CCNE1 amplification, HER2 amplification, RET fusion, and mutations in TP53, BRAF, PIK3CA, and KRAS, among others. These mechanisms may involve EGFR alternative bypass pathway activation, downstream pathway activation, oncogene fusion, or cell-cycle gene mutation, contributing to resistance to osimertinib.
In the included studies, these mechanisms were reported as acquired resistance mechanisms or acquired alterations as defined by the study authors, although some variation in the characterization was observed. For example, T790M loss was reported as a resistance mechanism, an alteration at progression, or a mediator of resistance. Variations in the occurrence of these mutations were observed across different lines of osimertinib treatment.
Additionally, multiple co-existing molecular alterations were observed in varying proportions across the included studies, both when osimertinib was administered as first- and second-line therapy. The heterogeneity and co-occurrence of multiple resistance mechanisms constitute a major challenge in developing an efficient treatment strategy to counteract tumor progression. The development of acquired resistance has limited the durability of clinical benefit experienced in patients treated with osimertinib and other TKIs for a/mNSCLC. The available data about resistance mechanisms especially to osimertinib or other TKIs are inconsistent, and published reports have suggested that treatment-naïve patients who progressed on osimertinib or other TKIs should be better characterized. Considering that the effectiveness of osimertinib in patients with a/mNSCLC is limited by the development of a heterogenous array of resistance mutations, there is a need for therapies that can mitigate the development of resistance to first-line osimertinib and/or broadly target the multitude of resistance mechanisms that are acquired after first-line osimertinib.
This SLR highlights several important gaps in the evidence. First, there is paucity of evidence relating to the impact of resistance mechanisms on clinical outcomes for patients with EGFR-mutated NSCLC. Of all the studies included in this SLR, none were specifically designed to measure the impact of resistance mechanisms on clinical outcomes such as ORR, CR, and PR. Second, factors such as race/ethnicity, social determinants of health, smoking status, and presence of brain metastases were infrequently reported. More evidence is needed to understand the impact of resistance mechanisms on clinical outcomes for patients with EGFR-mutated NSCLC, as well as patient, social, and behavioral factors that may be associated with particular resistance mechanisms. Finally, more evidence is needed to understand the occurrence of brain metastases by resistance mechanism, a common complication among patients with NSCLC.
This SLR has a few limitations. First, this SLR focused on studies that include US populations; therefore, the results of this SLR may not be generalizable globally. Second, the included studies are heterogenous in terms of study and patient characteristics, which could have an impact on the consistency of the results. However, when presenting the results, we have indicated data from individual studies to show the overall trend and potential outliers. In addition, there was limited evidence identified that focused exclusively on treatments other than osimertinib, but that is reflective of the current treatment practice, as our SLR included publications between 2018 and 2022.

5. Conclusions

The available literature on resistance mechanisms associated with current NSCLC treatments, primarily osimertinib, reveals molecular patient profiles that are heterogenous and complex, which may pose challenges in improving clinical outcomes in these patients in the US. While the evidence is limited, some resistance mutations have been associated with worse PFS, such as MET amplification, RET fusion, HER2 amplification, and PIK3CA mutation in patients on first-line osimertinib. In addition, T790M loss was associated with worse PFS in patients on 2L osimertinib after a prior EGFR TKI. These findings highlight the need to address both EGFR-dependent and EGFR-independent resistance mechanisms to improve outcomes for patients with EGFR-mutated a/mNSCLC.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/curroncol32040191/s1, Figure S1: Summary of the Cochrane Risk of Bias Assessment for Randomized Trials (RoB2). Table S1: Search strategy for OVID-based searches. Table S2: Newcastle-Ottawa scale assessment for non-randomized studies. Table S3: Study and patient characteristics (continuation). Table S4: Resistance mutation profile for patients who received first-line osimertinib. Table S5: Resistance mutation profile for patients who received second-line osimertinib. Table S6: Resistance mutation profile for patients who received first-line osimertinib and beyond. Table S7: Resistance mutation profile for patients who received second-line osimertinib and beyond. Table S8: Resistance mutation profile for patients who received TKIs or non-TKIs, where osimertinib was one of the treatment options. Table S9: Resistance mutation profile for patients who received other TKIs or non-TKIs. Table S10: Resistance mutation profile for patients who received unspecified treatment. Table S11: Studies that reported the impact of acquired resistance on clinical outcomes. References [8,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59] are cited in the supplementary materials.

Author Contributions

Conceptualization, methodology, project administration, resources, supervision, and writing—review and editing, P.V.; conceptualization, funding acquisition, methodology, project administration, resources, supervision, and writing—review and editing, J.V.; conceptualization, methodology, project administration, resources, supervision, and writing—review and editing, D.W.; conceptualization, methodology, software, validation, formal analysis, investigation, resources, data curation, writing—original draft, writing—review and editing, project administration, and supervision, J.U.; conceptualization, methodology, software, validation, formal analysis, investigation, resources, data curation, writing—original draft, writing—review and editing, project administration, and supervision, Y.K.; software, formal analysis, resources, data curation, writing—original draft preparation, and visualization, A.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research and the article processing charges were funded by Johnson & Johnson.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The original contributions presented in this study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

Conflicts of Interest

Pratyusha Vadagam, Dexter Waters, and Julie Vanderpoel are employees of Johnson & Johnson. Anil Bhagat, Yuting Kuang, and Jennifer Uyei are employees of IQVIA Inc. IQVIA Inc. received funding from Johnson & Johnson to conduct this study. The funders of the study participated in the design of the study, the writing of the manuscript, and the decision to publish the results. The funders had no role in the collection, analyses, or interpretation of the data.

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Curroncol 32 00191 g001
Figure 1. PRISMA flow diagram.
Figure 1. PRISMA flow diagram.
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Figure 2. Resistance mechanisms for patients who received first-line osimertinib. n = number of studies that reported each resistance mutation; the blue bars show the range for proportion of patients with a detected resistance mutation across studies; the yellow diamonds indicate the proportion of patients with a specific resistance mutation in each study for cases with multiple studies; C797X: broad category inclusive of C797S and C797G mutations.
Figure 2. Resistance mechanisms for patients who received first-line osimertinib. n = number of studies that reported each resistance mutation; the blue bars show the range for proportion of patients with a detected resistance mutation across studies; the yellow diamonds indicate the proportion of patients with a specific resistance mutation in each study for cases with multiple studies; C797X: broad category inclusive of C797S and C797G mutations.
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Figure 3. Resistance mechanisms for patients who received second-line osimertinib. n = number of studies that reported each resistance mutation; the blue bars show the range for proportion of patients with a detected resistance mutation across studies; the yellow diamonds indicate the proportion of patients with a specific resistance mutation in each study for cases with multiple studies; C797X: broad category inclusive of C797S and C797G mutations.
Figure 3. Resistance mechanisms for patients who received second-line osimertinib. n = number of studies that reported each resistance mutation; the blue bars show the range for proportion of patients with a detected resistance mutation across studies; the yellow diamonds indicate the proportion of patients with a specific resistance mutation in each study for cases with multiple studies; C797X: broad category inclusive of C797S and C797G mutations.
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Table 1. Study and patient characteristics.
Table 1. Study and patient characteristics.
Author Year; CountryLoT; TreatmentStudy Design Study PeriodNSex, Male %Age, Years-Median (Range)
Osimertinib
Cardona 2022; international [18]1L; osimertinibRWE/observationalNR9454.3%59.0 (31.0–84.0)
Piotrowska 2022; US [37]1L; osimertinibRWE/observationalNovember 2016–January 20225429.6%61.0
Ramalingam 2018; international [54]1L; osimertinibSingle-arm clinical trial4 March 2013–30 December 20226025.0%63.5 (38.0–91.0)
Bauml -a 2021; US, Canada [17]1L+; osimertinibRWE/observationalNR79932.3%63.0 (30.0–95.0)
Le 2018; US [27,60,61]1L+; osimertinibRWE/observationalJanuary 2011–February 201811828.0%63.0 (36.0–88.0)
Patil 2019; US [34]1L+; osimertinibRWE/observationalNR9533.7%NR
Schoenfeld 2019; US [42]1L+; osimertinibRWE/observationalJanuary 2016–December 201871NRNR
Ramalingam 2022; US [39]1L or 2L; osimertinibRWE/observationalJuly 2014–June 20212050NRNR
Oxnard 2018; US [33]2L-3L; osimertinibRWE/observationalNovember 201715147.0%NR
Lim 2021; US, Korea [29]2L+; osimertinibRWE/observationalNR55NRNR
Zhao 2018; US, China [50]2L+; osimertinibRWE/observationalJanuary 2017–October 2017293NRNR
Guibert 2018; US [22]Unspecified; osimertinibRWE/observationalNR46NRNR
Janne 2021; US [25,62]Unspecified; osimertinibRWE/observationalDecember 2014–November 2020755NRNR
Strohbehn 2019; US [44]Unspecified; osimertinibRWE/observationalNR28NRNR
Zhang 2018; US, China [49]Unspecified; osimertinibRWE/observationalNR110NRNR
Osimertinib included as one treatment option among patients treated with TKIs
Mondaca 2019; US [32]1L; erlotinib, afatinib, gefitinib, osimertinib, rociletinib, and nazartinibRWE/observationalJanuary 2016–August 201717735.0%66.0 (38.0–91.0)
Robichaux 2021; US [40]1L; EGFR TKIs (osimertinib and other TKIs)RWE/observationalNR16,715NRNR
Soria 2018; international [8,63,64]1L; osimertinib and SoC (gefitinib and erlotinib)Randomized clinical trial3 December 2014–30 December 202255637.1%64.0 (2.06–93.0)
Le 2022; international [16]1L+; tepotinib + osimertinib, and/or gefitinibRWE/observationalNR1225.0%69.5 (47.0–86.0)
Markovets 2021; international [57,65]1L+; osimertinib + savolitinibNon-randomized clinical trial5 August 2014–30 December 202218041.1%61.0 (28.0–92.0)
Piotrowska 2018; US [36]1L+; osimertinib and BLU667 + osimertinibRWE/observationalJuly 2014–August 20184137.0%64.0 (40.0–87.0)
Hochmair 2018; international [24,66,67,68,69]1L and 2L; afatinib and osimertinibRWE/observational28 December 2017–31 May 201820446.1%60.0 (30.0–86.0)
Rotow 2021; US [41]2L+; osimertinib + selpercatinibRWE/observationalNR12NRNR
Goldberg 2018; US [21]Unspecified; EGFR TKIs (afatinib, osimertinib, gefitinib, erlotinib, and rociletinib)RWE/observationalNR2937.9%60.0 (38.0–87.0)
Mack 2020; US [30]Unspecified; EGFR TKIs (erlotinib, afatinib, gefitinib, osimertinib, rociletinib, and others)RWE/observationalJune 2014–October 2016838843.0%NR
Yang 2021; international [46]Unspecified; afatinib post-osimertinibRWE/observationalNR1023NRNR
Yao 2019; US [47]Unspecified; EGFR TKIs (gefitinib, osimertinib, Lenvatinib, or other EGFR TKIs)RWE/observational2016–20183600NRNR
Yu 2022; US [48]Unspecified; gefitinib, afatinib, erlotinib, or osimertinibRWE/observational1 August 2005–1 August 2020944.4%60.0
Osimertinib included as one treatment option in patients treated with TKIs and/or non-TKIs
Mambetsariev 2022; US [31]1L+; erlotinib, osimertinib, afatinib, carboplatin/pemetrexed, and carboplatin/pemetrexed/pembrolizumabRWE/observational2014–2021944.4%60.0 (35.0–72.0)
Roper 2020; US [58,70,71,72]1L or 2L; osimertinib and local ablative therapy (LAT)Non-randomized clinical trial13 April 2016–20 September 202234NRNR
Papadimitrakopoulou 2018; international [59,73]2L; osimertinib and platinum-based doublet chemotherapyRandomized clinical trial4 August 2014–15 April 201641935.8%Mean (SD): 61.7 (11.7)
Patil 2020; US [35]Unspecified; EGFR TKIs: erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib
Immune checkpoint inhibitors: pembrolizumab, nivolumab, or atezolizumab as single agents or in combination with chemotherapy		RWE/observationalJune 2009–March 2019 570NRNR
Schrock 2018; US [43]Unspecified; with or without EGFR TKIs (erlotinib, ASP8273 or afatinib + cetuximab or afatinib or erlotinib, and osimertinib)RWE/observationalJune 2012–October 20173138.7%64.0 (46.0–77.0)
Other TKIs
Elamin 2022; US [51,74]1L+; poziotinibSingle-arm clinical trial17 March 2017–1 March 20235040.0%62.0 (29.0–77.0)
Helman 2018; international [23]1L+; rociletinibRWE/observationalEnrolled as of 1 July 20157728.6%61.0 (37.0–82.0)
Lu 2021; US [52]1L+; aumolertinibSingle-arm clinical trial8 May 2017–November 2022244NRNR
McCoach 2021; US [53]Unspecified; capmatinib + erlotinibSingle-arm clinical trial2013 to 20203540.0%65.0 (39.0–89.0)
Other TKIs with non-TKIs
Bauml-b 2021; international [55,75]2L and 3L; amivantamab + lazertinibNon-randomized clinical trial24 May 2016–26 January 2024161NRNR
Non-TKIs
Janne 2022; international [56]1L+; patritumab deruxtecan (HER3-DXd)Non-randomized clinical trial30 October 2017–31 December 20238135.8%64 (40–80)
Treatment/therapy name unspecified
Gaut 2018; US [20]1L or 2L; TKIs and chemotherapyRWE/observationalApril 2012–October 20169728.9%Mean: 66.7
Chiang 2020; US [19]1L or 2L+; 1st- and 2nd-generation EGFR TKIsRWE/observational1 November 2015-30 September 201778236.4%69.0
Jin 2019; international [26,76]Unspecified; EGFR TKIsRWE/observationalNR64NRNR
Li 2019; US [28]Unspecified; NRRWE/observationalJanuary 2015–December 201513685.5%68.0 (23.0–85.0)
Raez 2022; US [38,77]Unspecified; EGFR TKIsRWE/observationalNR3223NRNR
Suero-Abreu 2018; US [45]Unspecified; NRRWE/observationalSeptember 2015–January201811543.0%68.0
Abbreviations: 1L: first-line therapy; 1L+: first-line therapy and beyond; 2L: second-line therapy; 2L+: second-line therapy and beyond; 3L: third-line therapy; EGFR: epidermal growth factor receptor; LoT: line of therapy; NR: not reported; RWE: real-world evidence; SoC: standard of care; TKI: tyrosine kinase inhibitor; US: United States.
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Vadagam, P.; Waters, D.; Bhagat, A.; Kuang, Y.; Uyei, J.; Vanderpoel, J. Resistance Mutation Profiles Associated with Current Treatments for Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer in the United States: A Systematic Literature Review. Curr. Oncol. 2025, 32, 191. https://doi.org/10.3390/curroncol32040191

AMA Style

Vadagam P, Waters D, Bhagat A, Kuang Y, Uyei J, Vanderpoel J. Resistance Mutation Profiles Associated with Current Treatments for Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer in the United States: A Systematic Literature Review. Current Oncology. 2025; 32(4):191. https://doi.org/10.3390/curroncol32040191

Chicago/Turabian Style

Vadagam, Pratyusha, Dexter Waters, Anil Bhagat, Yuting Kuang, Jennifer Uyei, and Julie Vanderpoel. 2025. "Resistance Mutation Profiles Associated with Current Treatments for Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer in the United States: A Systematic Literature Review" Current Oncology 32, no. 4: 191. https://doi.org/10.3390/curroncol32040191

APA Style

Vadagam, P., Waters, D., Bhagat, A., Kuang, Y., Uyei, J., & Vanderpoel, J. (2025). Resistance Mutation Profiles Associated with Current Treatments for Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer in the United States: A Systematic Literature Review. Current Oncology, 32(4), 191. https://doi.org/10.3390/curroncol32040191

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