Next Article in Journal
Understanding the Barriers to Prostate Cancer Population-Based Early Detection Programs: The PRAISE-U BEST Survey
Previous Article in Journal
Dynamics of RAS Mutations in Liquid Biopsies in Metastatic Colorectal Cancer Patients—Case Series and Literature Review
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JPM
Volume 14
Issue 7
10.3390/jpm14070752
jpm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Systematic Review

EGFR-Tyrosine Kinase Inhibitor Retreatment in Non-Small-Cell Lung Cancer Patients Previously Exposed to EGFR-TKI: A Systematic Review and Meta-Analysis

by
Isabella Michelon
1,*,
Maysa Vilbert
2,
Caio Ernesto do Rego Castro
3,
Carlos Stecca
4,
Maria Inez Dacoregio
5,
Manglio Rizzo
6,7,
Vladmir Cláudio Cordeiro de Lima
8 and
Ludimila Cavalcante
9
1
Department of Medicine, Catholic University of Pelotas, Pelotas 96015-560, Brazil
2
Massachusetts General Hospital Cancer Center, Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
3
Department of Medicine, University of Brasilia, Brasília 70910-900, Brazil
4
Department of Medicine, Parana Oncology Center, Curitiba 80030-200, Brazil
5
Department of Medicine, University of Centro Oeste, Guarapuava 85040-167, Brazil
6
Cancer Immunobiology Laboratory, Instituto de Investigaciones en Medicina Traslacional, Universidad Austral-Consejo Nacional de Investigaciones Cientificas y Tecnologicas (CONICET), Buenos Aires 1428, Argentina
7
Clinical Oncology Unit, Hospital Universitario Austral, Av. Presidente Perón 1500, (B1629ODT) Derqui-Pilar, Buenos Aires 1428, Argentina
8
Department of Medical Oncology, AC Camargo Cancer Center, São Paulo 01509-010, Brazil
9
Department of Hematology and Medical Oncology, University of Virginia Comprehensive Cancer Center, Charlottesville, VA 22903, USA
*
Author to whom correspondence should be addressed.
J. Pers. Med. 2024, 14(7), 752; https://doi.org/10.3390/jpm14070752
Submission received: 9 June 2024 / Revised: 8 July 2024 / Accepted: 9 July 2024 / Published: 15 July 2024
(This article belongs to the Section Molecular Targeted Therapy)
Browse Figures
Versions Notes

Abstract

:
We performed a systematic review and meta-analysis to assess the efficacy of EGFR-tyrosine kinase inhibitors (TKI) retreatment in advanced/metastatic non-small-cell lung cancer (NSCLC) patients. We systematically searched PubMed, Embase, Cochrane databases, ASCO, and ESMO websites for studies evaluating EGFR-TKI retreatment in advanced/metastatic NSCLC patients. All analyses were performed using R software (v.4.2.2). We included 19 studies (9 CTs and 10 retrospective cohorts) with a total of 886 patients. In a pooled analysis of all patients during retreatment with TKI, median OS was 11.7 months (95% confidence interval [CI] 10.2–13.4 months) and PFS was 3.2 months (95% CI 2.5–3.9 months). ORR was 15% (95% CI 10–21%) and DCR was 61% (95% CI 53–67%). The subanalysis by generation of TKI in the rechallenge period revealed a slightly better ORR for patients on 3rd generation TKI (p = 0.05). Some limitations include the high heterogeneity of some of the analyses and inability to perform certain subanalyses. Our results unequivocally support the benefit of EGFR-TKI rechallenge in EGFR-mutated NSCLC patients progressing on TKI treatment after a TKI-free interval. These findings may be especially valuable in areas where access to novel therapeutic drugs and clinical trials is limited.

1. Introduction

Non-small-cell lung cancer (NSCLC) accounts for roughly 85% of all lung cancer diagnoses [1]. About 10 to 30% of NSCLC patients harbor epidermal growth factor receptor (EGFR) mutations, most commonly exon 19 deletions and exon 21 point mutations [2]. EGFR mutations activate a signaling pathway essential to cellular growth and differentiation, as well as to tumor progression and carcinogenesis [3]. The identification of these genetic alterations makes EGFR an attractive therapeutic target [2]. Thus, in the past decade, EGFR inhibition with tyrosine kinase inhibitors (TKI)s remarkably changed the treatment paradigm of NSCLC patients with EGFR driver mutations [4,5]. The benefit of TKIs also extends to other tumors [6,7,8]. These agents have proven efficacy and are used in first-line settings in several cancers, such as chronic myeloid leukemia and advanced renal cell carcinoma. Moreover, a synergistic effect is noted when combining TKIs with other kinase inhibitors or immunotherapy, as seen in metastatic melanoma and human epidermal growth factor receptor 2 (HER2)-positive breast cancer.
EGFR-TKIs reversibly or irreversibly bind to the tyrosine kinase domain of EGFR, preventing downstream signaling and leading to cell cycle arrest and eventually cell death [9]. First-generation TKIs, namely erlotinib and gefitinib initially led the way in advanced EGFR-mutated NSCLC [10]. An early phase III study on stage III or IV NSCLC treated with erlotinib in the first-line setting reported a decrease of 84% in the rates of progression compared to chemotherapy (hazard ratio (HR) for disease progression or death, 0.16, 95% CI (confidence interval) 0.10–0.26; p < 0.0001) [4]. Afatinib, a second-generation TKI, was also superior to chemotherapy, with a median progression-free survival (PFS) of 11.1 versus 6.7 months (HR 0.49, 95% CI, 0.37–0.65; p = 0.001) [11].
The third-generation TKI, osimertinib, significantly improved progression-free survival of NSCLC T790M-positive patients compared to platinum-based chemotherapy in the phase III AURA trial (HR 0.30, 95% CI 0.23–0.41, p < 0.001) [12]. In the first-line FLAURA study, a phase III trial, osimertinib demonstrated greater efficacy over other EGFR-TKIs, placing it as the preferred TKI single agent for advanced NSCLC [13]. Median PFS was 18.9 months for the osimertinib arm versus 10.2 months for the comparator regimen [13]. Similarly, overall survival (OS) was 38.6 months versus 31.8 months at 3-year follow-up [14].
The combination of third-generation TKIs with other agents is also currently being studied [15]. The phase III FLAURA-2 trial reported an improved median PFS for the combination of osimertinib plus chemotherapy compared to osimertinib alone of 25.5 months versus 16.7 months, respectively (HR 0.62; 95% CI 0.49–0.79; p < 0.001) [15]. Another first-line phase III trial, MARIPOSA, investigated the combination of amivantamab (an EGFR-MET bispecific antibody) and Lazertinib (a third-generation EGFR-TKI) compared to osimertinib [16]. The combination achieved a longer median PFS of 23.7 months versus 16.6 months for osimertinib, with a trend towards better OS [16].
Despite this array of therapeutic options, most patients will inevitably experience resistance and disease progression on an EGFR-TKI [9]. Several studies of EGFR-TKIs approved for the typical EGFR-sensitive mutations support that a drug-free interval may restore TKI sensitivity [17,18,19,20,21,22]. Therefore, re-exposure to TKIs in patients who have previously progressed on such treatments may offer a new chance of tumoral response and better outcomes. However, these studies may have been limited by a small sample size. Moreover, there is a lack of evidence on the real-world effectiveness of this strategy. Thus, this systematic review and meta-analysis aimed to evaluate the efficacy of EGFR-TKI retreatment following a TKI-free interval in NSCLC patients who were initially treated with EGFR-TKIs in the first-line setting on a clinical trial and in the real-world setting.

2. Materials and Methods

This study was performed following the guidelines from the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), and it was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the protocol number CRD42022383081 [23]. The complete PRISMA checklist can be found in Table S1.

2.1. Data Source and Search Strategy

A systematic search with no restriction regarding the publication date was performed in PubMed, Embase, and Cochrane databases in December of 2022. The search was last updated on 18 February 2024. The following combination of medical subject headings (MeSH) terms and boolean connectors were used: “non-small cell lung cancer” and (“TKI” or “tyrosine kinase inhibitors”) and (“retreatment” or “rechallenge”). The entire search strategy used as well as the version and link of each database can be found in Table S2. We have also searched references of all included studies and reviews.

2.2. Eligibility Criteria

All clinical trials and cohort studies analyzing the efficacy of EGFR-TKI retreatment in advanced/metastatic NSCLC patients who had progressed on a first-line TKI and on an interval-line of chemotherapy that reported any of the outcomes of interest were included. Studies analyzing TKI retreatment in the third or later line were included. Abstracts and conference presentations were also considered for inclusion. No restriction regarding the population size was made. Main exclusion criteria were as follows: (1) interruption of first-line TKI exclusively due to toxicity; (2) patients not treated with TKI in the first-line setting; (3) lack of interval chemotherapy between the first-line and rechallenge TKI; (4) lack of information regarding sequencing of TKI or chemotherapy; (5) outcomes of interest not reported; (6) case controls, case reports, case series, reviews, letters to the editor, and commentaries; and (7) manuscripts written in languages other than English.

2.3. Data Collection and Outcomes

Two authors (IM and CC) independently screened the articles using Zotero software and extracted the data from the studies included. A standardized Excel (version 16.86) sheet was used to collect each study’s population baseline characteristics and outcomes data. All inconsistencies between the authors were resolved by consensus or by consulting a third author (MV). We extracted data for pooled analysis on the following outcomes: (1) PFS; (2) OS; (3) objective response rate (ORR); (4) disease control rate (DCR); (5) duration of response (DOR); and (6) adverse events (AEs).
Subgroup analyses were performed according to (1) the design of the studies (CTs versus observational studies); (2) mutational status (EGFR sensitive mutations, T790M mutation, and mutational status unknown); (3) TKI choice in the rechallenge setting (same TKI versus a different TKI for the rechallenge); (4) first/second versus third-generation TKI; and (5) DCR in patients who initially achieved DCR with first TKI.

2.4. Quality Assessment

The ROBINS-I tool was used to assess the risk of bias in prospective clinical trials and observational cohort studies [24]. Two authors (IM and CC) independently completed the risk of bias assessment. Inconsistencies between the authors were resolved by consensus or by consulting a third author (MV). Following this protocol, each study was classified as low, moderate, serious, critical risk of bias or no information based on seven domains: bias due to confounding, selection of participants into the study, classification of interventions, deviations from intended intervention, missing data, in the measurement of outcomes and the selection of the reported result [24]. To verify the existence of publication bias, Egger’s test and funnel plots of individual study weights against point estimates were used.

2.5. Statistical Analysis

We performed proportional meta-analyses for binary outcomes and reported them in percentages of events with 95% CI. Logit-transformation of data was used when the individual study proportion was smaller than 0.2 or higher than 0.8. In the case of a study with zero events, we used the doubled-arcsine transformation. R software (version 4.2.2) was used to perform all statistical analyses. Pooled analysis of individual studies’ OS and PFS was carried out using medians with 95% CIs. The following packages were used: “metafor”; “meta”; “weight”; and “metagen”. I2 statistics were used to assess the heterogeneity; I2 > 25% were considered significant for heterogeneity. DerSimonian and Laird random-effects models were used in all analyses.

3. Results

3.1. Systematic Review

Initially, we identified 826 studies through our search strategy. After the removal of duplicates and exclusion by title and abstract, 51 studies were included for a comprehensive review. Finally, 19 studies met our eligibility criteria—nine prospective clinical trials and ten retrospective cohorts (Figure 1) [17,18,19,20,21,22,25,26,27,28,29,30,31,32,33,34,35,36,37]. A list of excluded studies after a comprehensive review can be found in the Supplementary Materials (Table S3) [38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69].

3.2. Baseline Characteristics

Of the 886 patients included, most were female (67.2%, n = 499/743), non-smokers (73.8%; n = 498/675), had adenocarcinoma (97.9%; n = 571/583), and received EGFR-TKI rechallenge as a third-line therapy (82.9%; n = 561/677). For most studies, data for metastatic sites and race or ethnicity were not available. The median age of each study ranged from 52 to 68 years. The median follow-up ranged from 7 to 38.9 months, and the TKI-free interval ranged from 5.9 to 13.8 months.
Osimertinib was used in the first-line and in the rechallenge setting in two studies. Gefitinib was the TKI of choice used in the first-line setting in seven studies. Of these, six studies also used gefitinib in the rechallenge. Erlotinib was used both in first-line and rechallenge in only one study. The ten remainder studies reported different TKIs in the first-line and in the rechallenge period. Baseline characteristics of included studies are presented in Table 1.
Most studies clearly defined that patients progressed on first-line TKI [17,18,19,20,21,25,26,28,29,30,31,32,33,34,36,37]. Among three studies, two did not specify the reason for TKI interruption, whereas one study stated that TKI rechallenge was administered after disease progression or unacceptable toxicity on first-line treatment [22,27,35].

3.3. Efficacy Outcomes

In patients who were retreated with any TKI, the pooled analysis of seven studies revealed a median OS of 11.7 months (95% CI 10.2–13.4 months), and in the analysis of ten studies, the median PFS was 3.2 months (95% CI 2.5–3.9 months) (Figure 2). The subgroup analysis of nine studies considering only patients re-exposed with first- or second-generation TKIs revealed a PFS of 3.1 months (95% CI 2.4–3.9 months) (Figure 2B). Only one study analyzed patients retreated with 3rd generation TKIs and reported a PFS of 4.1 months (95% CI 2.2–7.7 months) (p = 0.41, Figure 2B). Survival data from studies that could not be pooled for survival analyses are presented in Table S4.
Overall, the ORR across 18 studies was 15% (95% CI 10–21%), and no significant interaction was observed between observational studies and CTs (p = 0.69) (Figure 3A). In a subgroup analysis according to mutational profile, 556 patients harboring EGFR-sensitive mutations achieved an ORR of 15% (95% CI 9–23%), while 31 patients with the T790M mutation had an ORR of 18% (95% CI 0–55%). For the 174 patients with unknown mutational status, the ORR was 11% (95% CI 2–24%) (Figure 3B). No significant differences were observed between groups (p = 0.77) (Figure 3B). The analysis comparing rechallenge with different generations of TKI (15 studies on first/second- versus three studies on third-generation) revealed a borderline better ORR for 86 patients on third-generation (26% [95% CI 15–40%], I2 = 72%) TKI compared to 714 patients on first/second-generation (14% [95% CI 9–20%], I2 = 30%) (p = 0.05; Figure 3C). Individuals re-exposed to the same TKI as the first-line treatment presented with comparable responses to individuals treated with a different drug (p = 0.99) (Figure 3D).
A pooled analysis of 18 studies showed that 61% of individuals (95% CI 53–67%) achieved a DCR, with no significant differences between observational studies and clinical trials (p = 0.46) (Figure 4A). In a subgroup analysis according to mutational status, 558 individuals harboring EGFR-sensitive mutations had a DCR of 60% (95% CI 49–71), whereas 31 with positive T790M had a DCR of 61% (95% CI 42–77%), and 174 with unknown mutational status, a DCR of 50% (95% CI 43–58%), with no significant differences seen among groups (p = 0.27) (Figure 4B). The analysis for DCR in 714 patients (16 studies) treated with first/second- versus 86 patients (three studies) on third-generation TKI showed a similar DCR of about 60% for both (p = 0.64; Figure 4C). The DCR was also similar for individuals treated with the same or a different TKI in the rechallenge period (p = 0.85; Figure 4D)
The subanalysis that included 284 patients who previously achieved DCR during first-line treatment revealed a DCR of 59% (95% CI 49–68%) with rechallenge (Figure S1). The median duration of response to TKI rechallenge was described in only five studies, and it ranged from 2.2 to 4.4 months, as presented in Table S5.
Analyses stratified by TKI-free intervals were reported in five studies, and the information available is described in Table S6. In total, 3 studies with 52 patients found no correlation between TKI-free intervals and response or survival rates [19,28,34]. In 2 studies, 273 patients rechallenged after a longer TKI-free period had better response or survival rates compared to shorter intervals [22,30].

3.4. Adverse Events

The most common any-grade adverse events were skin toxicity and diarrhea (Figure S2). For both, the incidence of grade 1–2 AEs was significantly more common than grade 3 or higher (p ≤ 0.01) (Figure S2).

3.5. Quality Assessment

Four studies were judged to be at serious risk of bias, mostly due to the retrospective design and lack of adjustment for confounding factors (Table S7) [21,26,31,34]. The other 15 studies (6 retrospective and 9 prospective non-randomized trials) were at moderate risk of bias [17,18,19,20,22,25,27,28,29,30,32,33,35,36,37]. In the funnel plot analysis for ORR, a wide distribution of studies was seen (Figure S4). However, the Egger’s test showed no indication of publication bias (z = 0.93; p = 0.35).

4. Discussion

To the best of our knowledge, this systematic review and meta-analysis is the first to evaluate advanced NSCLC patients undergoing TKI retreatment after progression on initial TKI and interval line of chemotherapy. Our comprehensive meta-analysis revealed a median overall survival of about a year for retreatment in the third line or later, an ORR of 15%, and a favorable DCR of 61%. Patients who previously achieved DCR in their initial TKI therapy exhibited a noteworthy 59% DCR upon retreatment. Additionally, those retreated with third-generation TKI demonstrated the highest ORR at 26% and a DCR of 64%. Among patients harboring EGFR-sensitive mutations, 60% DCR was observed with TKI rechallenge. Retreatment with either the same or a different TKI demonstrated comparable efficacy, with no significant differences observed between study designs, mutational statuses, or whether patients were re-exposed to the same first-line TKI or a different one. The safety profile was similar to that observed in previous studies on TKI monotherapy in earlier settings [4,11,12].
In NSCLC patients harboring EGFR mutations, a significant benefit over chemotherapy was observed with EGFR-TKI in the first-line setting [4,11,70,71,72]. The most remarkable predictor of TKI response is EGFR mutational status, particularly exon 19 deletion and L858R point mutation in exon 21 [73,74,75]. A phase III trial reported a 70% improvement in PFS in patients receiving gefitinib compared to those on carboplatin-paclitaxel [70]. The EGFR-TKI group also exhibited higher response rates (89.5% versus 79.8%). Despite initial positive responses, most patients eventually face disease progression within the first or second year of treatment due to acquired resistance [76].
The clinical benefit of EGFR-TKIs in advanced NSCLC patients is influenced by genetic, clinical, and pathological factors [73,77]. Compared to other histological types, adenocarcinoma frequently presents with a better prognosis [73,74,75]. Non-smokers, females, and patients of Asian descent are known to derive the highest benefit from EGFR-TKIs [78,79]. Moreover, previous lines of therapy and resistance mechanisms (e.g., acquired T790M mutation) may influence the effectiveness of subsequent strategies [80,81]. In this meta-analysis, a high number of patients had adenocarcinoma, were female, and were non-smokers. However, we could not perform subgroup analyses based on all these factors due to lack of patient level data from individual studies.
In EGFR-mutated NSCLC, alterations within the EGFR domains and downstream pathways drive malignant cell survival. Emerging evidence indicates that NSCLC may harbor mutated and non-mutated EGFR clones in the same tumor tissue [82]. During TKI treatment, sensitive cells are suppressed, and eventually, resistant cells begin to proliferate, which are then targeted by subsequent therapies [17,83]. Following a period free of TKIs, EGFR-sensitive clones are prone to re-growth [36]. As tumors regain sensitivity, TKI re-treatment may once again effectively target tumoral cells [17,18,36]. Another rationale for TKI rechallenge benefit relies on oncogene addiction [84]. This theory explains that despite the extensive genetic and epigenetic modifications seen in several tumors, blocking just one mutation can inhibit cancer cells from growth and proliferation [84]. This is attributed to the fact that tumor survival is often linked to one or few driver oncogenes, and targeting them may more precisely prevent disease progression [84].
Drug rechallenge, particularly with targeted therapies, has arisen as a potential strategy to increase disease control in refractory patients who have progressed on multiple lines of therapy. Reintroduction of the same therapy has been reported in melanoma, colorectal cancer, and renal cell carcinoma [85,86,87,88,89,90]. A meta-analysis including 400 patients with BRAF-mutated advanced melanoma showed a 65% DCR with rechallenge of BRAF and MEK inhibitors in later lines [91]. It also showed a median survival of 9.8 months and that a targeted therapy free interval of 6 months or more was associated with a greater DCR [91]. The largest cohort included in our current meta-analysis explored EGFR-TKI rechallenge in 205 advanced or metastatic NSCLC patients [22]. Median OS and PFS were 12.6 and 4.1 months, respectively, and the DCR was 44.4%. Overall, our pooled analyses found a median OS and PFS of 11.7 and 3.2 months, respectively, and a 61% DCR. Additionally, the AEs most often reported among studies were skin toxicity and diarrhea, consistent with prior studies on EGR-TKI in the first line [4,11,12]. For both, grade 1–2 events were significantly more common than grade 3. Thus, our findings support retreatment with EGFR-TKI as a viable therapeutic strategy for patients who progressed on previous TKI and other lines of therapy. Importantly, the rechallenge appears to be well tolerated, without additional toxicity. This is especially important for low- and middle-income countries with more limited options, where the newest therapies and clinical trials may not be readily accessible.
Multiple mechanisms are involved with tumoral-acquired resistance. However, most are not well understood [76,92]. In the scenario of EGFR-mutated NSCLC, acquired resistance can be classified as target or target-dependent and off-target or target-independent [93,94,95]. The first develops within the kinase domain of EGFR. The latter involves targets other than the kinase domain (e.g., bypass mechanisms and phenotypic transformation) [93,94,95]. Off-target resistance is more frequently seen in patients on third-generation TKI, whereas on-target resistance is seen in patients on first- and second-generation TKI [93,94,95]. In contrast, some evidence has shown that over 50% of patients with acquired resistance to first or second-generation TKIs develop new mutations within the drug domain [76].
One of the most common resistance on-target mutations to first- and second-generation TKIs is T790M, which affects the EGFR binding and enzymatic site [76,82]. Previous studies have consistently associated the presence of T790M with a poor prognosis [5,26]. However, findings from the AURA3 trial demonstrated that NSCLC patients harboring T790M mutations and treated with osimertinib achieved a great response, with an ORR of 71% after progressing on first-line EGFR-TKI therapy [12]. This underscores the sensitivity of T790M to the 3rd generation TKI osimertinib. In our study, the subgroup analysis of 31 patients carrying T790M mutations previously treated with various TKIs revealed a DCR of 61%.
Osimertinib has consistently demonstrated notable efficacy in the rechallenge scenario [20,31,35]. In our search, we found three studies assessing the response of osimertinib in this specific context, encompassing two retrospective studies and one prospective trial [20,31,35]. Uy et al. and Ichihara et al., both observational retrospective cohorts, reported response rates ranging from 12 to 33% and DCR spanning from 47 to 74%, whereas OSIRS, a phase II study, reported ORR and DCR values of 31.5% and 69%, respectively [20,31,35]. Our study found an ORR of 26% and a DCR of 64% in the subgroup of patients rechallenged with osimertinib.
One study included patients who were retreated with afatinib [19]. In the phase II trial conducted by the Okayama Lung Cancer Study Group, 12 patients retreated with afatinib achieved an ORR of 17% and a remarkable DCR of 92% [19]. Results from an ongoing phase II multicenter study—the REAL study, with a target enrollment of 30 patients—are awaited to better address the role of afatinib rechallenge in patients progressing after first-line osimertinib (UMIN000049225) [67].
Some ways to overcome resistance include combinations of TKI with other targeted therapies, chemotherapy, and local therapies [5,9,76,96,97]. Emerging methods, such as circulating tumor DNA/RNA and sequencing of oncogenic drivers, may identify targets early in the scenario of acquired resistance and provide some directions for better treatment selection [83,98]. Results from the ongoing ORCHARD, a phase II study investigating strategies based on the tumor molecular profile for advanced NSCLC patients who progressed on first-line osimertinib, may address some of these questions (NCT03944772) [99].
Despite recent advances, treating metastatic EGFR mutant NSCLC patients progressing on first-line TKI is still challenging [5]. The MARIPOSA-2 trial has investigated a promising combination therapy of amivantamab-chemotherapy plus lazertinib or amivantamab-chemotherapy compared to chemotherapy alone in patients after progression to osimertinib and has shown improved PFS and intracranial PFS [100]. Another very important question is regarding the continuation of osimertinib following first-line progression [101,102]. This has been investigated in ongoing clinical trials combining osimertinib with several agents [103]. Regarding third-line therapy for EGFR-mutant NSCLC patients, previously treated with EGFR-TKI and platinum-based chemotherapy, a novel antibody-drug conjugate patritumab deruxtecan, or HER3-DXd, has been evaluated in the phase II HERTHENA-Lung01 [104]. Patients on HER3-DXd achieved an ORR of 29.3%, a median PFS of 5.5 months, and a median OS of 11.9 months [104]. Our study of TKI rechallenge in the third or later line showed a similar median OS (11.7 months) to HERTHENA-Lung01, showing that TKI retreatment may benefit patients with limited therapeutic options after disease progression.
The therapeutic landscape of EGFR-mutated NSCLC has dramatically changed with the addition of promising new therapies and advances in precision medicine. Nonetheless, these groundbreaking discoveries are accompanied by vast disparities between patients in different countries or from different socio-economic backgrounds [105,106,107,108,109]. Middle- and low-income countries have limited access to targeted therapies, significant barriers in performing molecular diagnostic tests, and worse cancer treatment outcomes compared to high-income countries [105,106,107,108,109]. Additionally, pre-existing discrepancies in cancer care are likely to widen as treatment paradigms grow increasingly more complex and costly [109]. Our meta-analysis demonstrating the benefit of EGFR-TKI in the rechallenge scenario may be of special value in locations with limited access to new therapeutic developments, but research and initiatives to increase access to cancer therapies and oncological care around the world should grow concurrently with new drug development efforts.
While our study provides valuable insights, it is essential to acknowledge certain limitations. The unavailability of data from individual studies hindered our ability to perform subanalyses based on crucial factors such as drug-free time or the number of chemotherapy cycles. Moreover, appreciable heterogeneity was observed in some analyses, likely related to inclusion of observational and small-size studies. Nonetheless, in recognition of these limitations, we implemented random-effects models across all analyses to mitigate potential biases. Furthermore, we conducted separate analyses based on the studies’ design and other relevant subgroups to enhance our findings’ robustness and reliability. Further prospective studies on EGFR-TKI rechallenge should focus on better stratification of patients and assessment of response according to important clinicopathological factors (e.g., age, gender, ethnicity, smoking, mutational status, previous lines of therapies, and TKI-free interval).

5. Conclusions

Our meta-analysis represents the first comprehensive assessment of TKI re-exposure in patients with NSCLC who progressed on both first-line TKI and subsequent therapy. The results suggest that advanced EGFR-mutated NSCLC patients who experience treatment failure with initial TKI treatment may derive benefit from rechallenge with an EGFR-TKI following a TKI-free interval. Importantly, our analysis indicates that the effectiveness of re-exposure remains consistent whether with the same or a different TKI. These findings contribute valuable insights into potential therapeutic strategies for this patient population, especially when access to novel therapeutic drugs and clinical trials is limited.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jpm14070752/s1; Table S1—Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist for the manuscript (A), and the abstract (B); Table S2—Full search strategy used in each database: (A) Pubmed; (B) Cochrane; (C) Embase; (D) ESMO; (E) ASCO; Table S3—List of studies excluded after full review; Table S4—Median OS (A) and median PFS (B) of individual studies for NSCLC patients treated with EGFR-rechallenge; Table S5—Median duration of response of TKI rechallenge according to individual studies; Table S6—Efficacy outcomes according to the TKI-free interval between the first-line and rechallenge TKI for individual studies; Table S7—Quality assessment of studies using the risk of bias summary for non-randomized studies (ROBINS-I) tool. Figure S1—DCR during rechallenge in the subgroup of patients who previously achieved DCR with initial TKI; Figure S2—Frequency of adverse events stratified by grade: (A) skin toxicity; and (B) diarrhea; and Figure S3—Funnel plot analysis of objective response rate (ORR) in NSCLC patients rechallenged with TKI.

Author Contributions

Conceptualization: I.M., M.V., C.E.d.R.C., M.I.D. and C.S.; methodology: I.M. and M.V.; software: I.M. and M.V.; validation: I.M., M.V. and C.E.d.R.C.; formal analysis: I.M., M.V. and C.E.d.R.C.; investigation: I.M. and C.E.d.R.C.; data curation: I.M., M.V. and C.E.d.R.C.; resources: I.M., M.V., C.E.d.R.C., M.I.D., C.S., M.R., V.C.C.d.L. and L.C.; visualization: I.M., M.V., C.E.d.R.C., M.I.D., C.S., M.R., V.C.C.d.L. and L.C.; writing—original draft: I.M., M.V., C.E.d.R.C., M.I.D., C.S., M.R., V.C.C.d.L. and L.C.; supervision: M.V., M.R., V.C.C.d.L. and L.C. All authors contributed to writing, reviewing, and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All research data presented in this study is accessible to the corresponding author upon request.

Acknowledgments

We thank Rhanderson Cardoso for his guidance and support in conducting a systematic review and meta-analysis.

Conflicts of Interest

The authors I.M., M.V., C.E.R.C., M.I.D. and C.S. declare no conflicts of interest. M.R. reports receiving honoraria and a consulting or advisory role for MSD Oncology, Janssen Oncology, and AstraZeneca, and travel accommodation and expenses from Takeda, Roche, and AstraZeneca. V.C.C.L reports consulting or advisory role for Janssen, MSD, BMS, Lilly, Astrazeneca, and Daichii-Sankyo. L.C. reports a consulting or advisory role for Actuate Therapeutics, Pliant Therapeutics, Janssen, and CDR-Life as well as stock and other ownership interests in Actuate Therapeutics.

Abbreviations

AEs, adverse events; Afa, afatinib; ASCO, American Society of Clinical Oncology; CI, confidence interval; CTs, clinical trials; DCR, disease control rate; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EGFR, epidermal growth factor receptor; Erl, erlotinib; ESMO, European Society for Medical Oncology; Gef, gefitinib; HR, hazard ratio; HER2, human epidermal growth factor receptor 2; Ico, icotinib; ICI, immune checkpoint inhibitors; MeSH, medical subject headings; mos, months; NSCLC, non-small cell lung cancer; NA, not available; N, number of patients; ORR, objective response rate; Osi, osimertinib; OS, overall survival; PRISMA, preferred reporting items for systematic reviews and meta-analyses.

References

  1. Molina, J.R.; Yang, P.; Cassivi, S.D.; Schild, S.E.; Adjei, A.A. Non-Small Cell Lung Cancer: Epidemiology, Risk Factors, Treatment, and Survivorship. Mayo Clin. Proc. 2008, 83, 584–594. [Google Scholar] [CrossRef]
  2. Mitsudomi, T.; Yatabe, Y. Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer Sci. 2007, 98, 1817–1824. [Google Scholar] [CrossRef]
  3. Thomas, A.; Rajan, A.; Giaccone, G. Tyrosine Kinase Inhibitors in Lung Cancer. Hematol./Oncol. Clin. N. Am. 2012, 26, 589–605. [Google Scholar] [CrossRef]
  4. Zhou, C.; Wu, Y.-L.; Chen, G.; Feng, J.; Liu, X.-Q.; Wang, C.; Zhang, S.; Wang, J.; Zhou, S.; Ren, S.; et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011, 12, 735–742. [Google Scholar] [CrossRef]
  5. Zhong, J.; Bai, H.; Wang, Z.; Duan, J.; Zhuang, W.; Wang, D.; Wan, R.; Xu, J.; Fei, K.; Ma, Z.; et al. Treatment of advanced non-small cell lung cancer with driver mutations: Current applications and future directions. Front. Med. 2023, 17, 18–42. [Google Scholar] [CrossRef]
  6. Pottier, C.; Fresnais, M.; Gilon, M.; Jérusalem, G.; Longuespée, R.; Sounni, N.E. Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy. Cancers 2020, 12, 731. [Google Scholar] [CrossRef]
  7. Ebrahimi, N.; Fardi, E.; Ghaderi, H.; Palizdar, S.; Khorram, R.; Vafadar, R.; Ghanaatian, M.; Rezaei-Tazangi, F.; Baziyar, P.; Ahmadi, A.; et al. Receptor tyrosine kinase inhibitors in cancer. Cell. Mol. Life Sci. 2023, 80, 104. [Google Scholar] [CrossRef]
  8. Huang, L.; Jiang, S.; Shi, Y. Tyrosine kinase inhibitors for solid tumors in the past 20 years (2001–2020). J. Hematol. Oncol. 2020, 13, 143. [Google Scholar] [CrossRef]
  9. Johnson, M.; Garassino, M.C.; Mok, T.; Mitsudomi, T. Treatment strategies and outcomes for patients with EGFR-mutant non-small cell lung cancer resistant to EGFR tyrosine kinase inhibitors: Focus on novel therapies. Lung Cancer 2022, 170, 41–51. [Google Scholar] [CrossRef]
  10. Karachaliou, N.; Fernandez-Bruno, M.; Bracht, J.W.P.; Rosell, R. EGFR first- and second-generation TKIs—There is still place for them in EGFR-mutant NSCLC patients. Transl. Cancer Res. 2018, 8, S23–S47. [Google Scholar] [CrossRef]
  11. Sequist, L.V.; Yang, J.C.-H.; Yamamoto, N.; O’Byrne, K.; Hirsh, V.; Mok, T.; Geater, S.L.; Orlov, S.; Tsai, C.-M.; Boyer, M.; et al. Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients with Metastatic Lung Adenocarcinoma with EGFR Mutations. JCO 2013, 31, 3327–3334. [Google Scholar] [CrossRef] [PubMed]
  12. Mok, T.S.; Wu, Y.-L.; Ahn, M.-J.; Garassino, M.C.; Kim, H.R.; Ramalingam, S.S.; Shepherd, F.A.; He, Y.; Akamatsu, H.; Theelen, W.S.M.E.; et al. Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer. N. Engl. J. Med. 2017, 376, 629–640. [Google Scholar] [CrossRef] [PubMed]
  13. Soria, J.-C.; Ohe, Y.; Vansteenkiste, J.; Reungwetwattana, T.; Chewaskulyong, B.; Lee, K.H.; Dechaphunkul, A.; Imamura, F.; Nogami, N.; Kurata, T.; et al. Osimertinib in Untreated EGFR -Mutated Advanced Non–Small-Cell Lung Cancer. N. Engl. J. Med. 2018, 378, 113–125. [Google Scholar] [CrossRef] [PubMed]
  14. Ramalingam, S.S.; Vansteenkiste, J.; Planchard, D.; Cho, B.C.; Gray, J.E.; Ohe, Y.; Zhou, C.; Reungwetwattana, T.; Cheng, Y.; Chewaskulyong, B.; et al. Overall Survival with Osimertinib in Untreated, EGFR -Mutated Advanced NSCLC. N. Engl. J. Med. 2020, 382, 41–50. [Google Scholar] [CrossRef] [PubMed]
  15. Planchard, D.; Jänne, P.A.; Cheng, Y.; Yang, J.C.-H.; Yanagitani, N.; Kim, S.-W.; Sugawara, S.; Yu, Y.; Fan, Y.; Geater, S.L.; et al. Osimertinib with or without Chemotherapy in EGFR -Mutated Advanced NSCLC. N. Engl. J. Med. 2023, 389, 1935–1948. [Google Scholar] [CrossRef]
  16. Cho, B.C.; Felip, E.; Spira, A.I.; Girard, N.; Lee, J.-S.; Lee, S.-H.; Ostapenko, Y.V.; Danchaivijitr, P.; Liu, B.; Alip, A.; et al. LBA14 Amivantamab plus lazertinib vs osimertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): Primary results from MARIPOSA, a phase III, global, randomized, controlled trial. Ann. Oncol. 2023, 34, S1306. [Google Scholar] [CrossRef]
  17. Song, Y.; Wu, Y.-L.; Cao, L.-J.; Chen, J.-H.; Ma, Z.-Y.; Cui, J.-W.; Wang, J.; Liu, H.-B.; Ding, J.-Y.; Hu, M. Efficacy and Safety of Gefitinib as Third-line Treatment in NSCLC Patients with Activating EGFR Mutations Treated with First-line Gefitinib Followed by Second-line Chemotherapy: A Single-Arm, Prospective, Multicenter Phase II Study (RE-CHALLENGE, CTONG1304). Am. J. Clin. Oncol. 2019, 42, 432–439. [Google Scholar] [CrossRef] [PubMed]
  18. Cappuzzo, F.; Morabito, A.; Normanno, N.; Bidoli, P.; Del Conte, A.; Giannetta, L.; Montanino, A.; Mazzoni, F.; Buosi, R.; Burgio, M.A.; et al. Efficacy and safety of rechallenge treatment with gefitinib in patients with advanced non-small cell lung cancer. Lung Cancer 2016, 99, 31–37. [Google Scholar] [CrossRef] [PubMed]
  19. Oda, N.; Hotta, K.; Ninomiya, K.; Minami, D.; Ichihara, E.; Murakami, T.; Yokoyama, T.; Ichikawa, H.; Chikamori, K.; Takigawa, N.; et al. A phase II trial of EGFR-TKI readministration with afatinib in advanced non-small-cell lung cancer harboring a sensitive non-T790M EGFR mutation: Okayama Lung Cancer Study Group trial 1403. Cancer Chemother. Pharmacol. 2018, 82, 1031–1038. [Google Scholar] [CrossRef]
  20. Ichihara, E.; Hotta, K.; Ninomiya, K.; Kubo, T.; Ohashi, K.; Rai, K.; Tanaka, H.; Tabata, M.; Maeda, Y.; Kiura, K. Re-administration of osimertinib in osimertinib-acquired resistant non-small-cell lung cancer. Lung Cancer 2019, 132, 54–58. [Google Scholar] [CrossRef]
  21. Kaira, K.; Kobayashi, K.; Shiono, A.; Yamaguchi, O.; Hashimoto, K.; Mouri, A.; Shinomiya, S.; Miura, Y.; Imai, H.; Kagamu, H. Effectiveness of EGFR-TKI rechallenge immediately after PD-1 blockade failure. Thorac. Cancer 2021, 12, 864–873. [Google Scholar] [CrossRef]
  22. Chang, G.-C.; Tseng, C.-H.; Hsu, K.-H.; Yu, C.-J.; Yang, C.-T.; Chen, K.-C.; Yang, T.-Y.; Tseng, J.-S.; Liu, C.-Y.; Liao, W.-Y.; et al. Predictive factors for EGFR-tyrosine kinase inhibitor retreatment in patients with EGFR-mutated non-small-cell lung cancer—A multicenter retrospective SEQUENCE study. Lung Cancer 2017, 104, 58–64. [Google Scholar] [CrossRef]
  23. Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.; Brennan, S.E.; et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021, 372, n71. [Google Scholar] [CrossRef]
  24. Sterne, J.A.; Hernán, M.A.; Reeves, B.C.; Savović, J.; Berkman, N.D.; Viswanathan, M.; Henry, D.; Altman, D.G.; Ansari, M.T.; Boutron, I.; et al. ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions. BMJ 2016, 355, i4919. [Google Scholar] [CrossRef] [PubMed]
  25. Asahina, H.; Oizumi, S.; Inoue, A.; Kinoshita, I.; Ishida, T.; Fujita, Y.; Sukoh, N.; Harada, M.; Maemondo, M.; Saijo, Y.; et al. Phase II study of gefitinib readministration in patients with advanced non-small cell lung cancer and previous response to gefitinib. Oncology 2010, 79, 423–429. [Google Scholar] [CrossRef]
  26. Becker, A.; Crombag, L.; Heideman, D.A.M.; Thunnissen, F.B.; van Wijk, A.W.; Postmus, P.E.; Smit, E.F. Retreatment with erlotinib: Regain of TKI sensitivity following a drug holiday for patients with NSCLC who initially responded to EGFR-TKI treatment. Eur. J. Cancer 2011, 47, 2603–2606. [Google Scholar] [CrossRef]
  27. Chen, Y.-M.; Lai, C.-H.; Rau, K.-M.; Huang, C.-H.; Chang, H.-C.; Chao, T.-Y.; Tseng, C.-C.; Fang, W.-F.; Chung, Y.-H.; Wang, Y.-H.; et al. Impact of clinical parameters and systemic inflammatory status on epidermal growth factor receptor-mutant non-small cell lung cancer patients readministration with epidermal growth factor receptor tyrosine kinase inhibitors. BMC Cancer 2016, 16, 868. [Google Scholar] [CrossRef]
  28. Koizumi, T.; Agatsuma, T.; Ikegami, K.; Suzuki, T.; Kobayashi, T.; Kanda, S.; Yoshikawa, S.; Kubo, K.; Shiina, T.; Takasuna, K.; et al. Prospective study of gefitinib readministration after chemotherapy in patients with advanced non-small-cell lung cancer who previously responded to gefitinib. Clin. Lung Cancer 2012, 13, 458–463. [Google Scholar] [CrossRef]
  29. Lee, S.Y.; Choi, J.; Lee, J.C.; Choi, C.M.; Kim, I.A.; Lee, K.Y.; Lee, J.E.; Jang, S.H.; Yoon, S.H.; Oh, I.-J.; et al. 24P Efficacy and safety of 1st generation EGFR TKI retreatment in EGFR mutation-positive, T790M-negative patients previously treated with 1st or 2nd generation EGFR TKI and cytotoxic chemotherapy. J. Thorac. Oncol. 2023, 18, S54. [Google Scholar] [CrossRef]
  30. Lee, Y.; Kim, H.Y.; Lee, S.-H.; Lim, K.Y.; Lee, G.K.; Yun, T.; Han, J.-Y.; Kim, H.T.; Lee, J.S. Clinical significance of heterogeneity in response to retreatment with epidermal growth factor receptor tyrosine kinase inhibitors in patients with lung cancer acquiring secondary resistance to the drug. Clin. Lung Cancer 2014, 15, 145–151. [Google Scholar] [CrossRef]
  31. Uy, N.F.; Tratt, M.; Eaton, K.D.; Santana-Davila, R.; Baik, C.S. Osimertinib rechallenge in advanced EGFR non-small cell lung cancer patients. JCO 2023, 41, e21196. [Google Scholar] [CrossRef]
  32. Oh, I.-J.; Ban, H.-J.; Kim, K.-S.; Kim, Y.-C. Retreatment of gefitinib in patients with non-small-cell lung cancer who previously controlled to gefitinib: A single-arm, open-label, phase II study. Lung Cancer 2012, 77, 121–127. [Google Scholar] [CrossRef]
  33. Song, Z.; Yu, X.; He, C.; Zhang, B.; Zhang, Y. Re-administration after the failure of gefitinib or erlotinib in patients with advanced non-small cell lung cancer. J. Thorac. Dis. 2013, 5, 400–405. [Google Scholar] [CrossRef] [PubMed]
  34. Tomizawa, Y.; Fujita, Y.; Tamura, A.; Shirai, M.; Shibata, S.; Kawabata, T.; Shibayama, T.; Fukai, S.; Kawahra, M.; Saito, R. Effect of gefitinib re-challenge to initial gefitinib responder with non-small cell lung cancer followed by chemotherapy. Lung Cancer 2010, 68, 269–272. [Google Scholar] [CrossRef] [PubMed]
  35. Soto Parra, H.; Noto, L.; Galetta, D.; Ferrau, F.; Gebbia, V.; Tassone, P.; Verderame, F.; Aiello, M.; Latteri, F.; Novello, S. A phase II, noncomparative, open label, multicentre, study of AZD9291 in patients with locally advanced or metastatic EGFR mutated “T790M undetectable or unknown” non-small cell lung cancer (stage IIIB-IV) after no immediate prior EGFR TKI (OSIRIS study). J. Clin. Oncol. 2017, 35, TPS9107. [Google Scholar] [CrossRef]
  36. Xia, G.-H.; Zeng, Y.; Fang, Y.; Yu, S.-R.; Wang, L.; Shi, M.-Q.; Sun, W.-L.; Huang, X.-E.; Chen, J.; Feng, J.-F. Effect of EGFR-TKI retreatment following chemotherapy for advanced non-small cell lung cancer patients who underwent EGFR-TKI. Cancer Biol. Med. 2014, 11, 270–276. [Google Scholar] [CrossRef]
  37. Yu, S.; Wang, Y.; Li, J.; Hao, X.; Wang, B.; Wang, Z.; Zhang, X.; Shi, Y. Gefitinib versus erlotinib as salvage treatment for lung adenocarcinoma patients who benefited from the initial gefitinib: A retrospective study. Thorac. Cancer 2013, 4, 109–116. [Google Scholar] [CrossRef] [PubMed]
  38. Nakashima, M.; Hirose, T.; Ohki, Y.; Murata, Y.; Sugiyama, T.; Ishida, H.; Okuda, K.; Yamaoka, T.; Ohmori, T.; Ohnishi, T. Clinical Benefit of 2ND EGFR-TKI Retreatment on Overall Survival in Patients with Advanced Non-Small Cell Lung Cancer. Ann. Oncol. 2013, 24, ix43. [Google Scholar] [CrossRef]
  39. Takeda, T.; Itano, H.; Saitoh, M.; Kohno, N.; Takemoto, T.; Hirata, K.; Tanaka, T.; Takeda, S. Second-generation EGFR-TKI (afatinib) rechallenge to overcome acquired resistance to first-generation EGFR-TKIs. Ann. Oncol. 2015, 26, vii137. [Google Scholar] [CrossRef]
  40. Kodani, M.; Igishi, T.; Sakamoto, T.; Touge, H.; Izumi, H.; Ito, S.; Kurai, J.; Yamaguchi, K.; Nakamoto, M.; Shimizu, E. Rechallenge with EGFR-TKI after a Drug Holiday, Retrospective Study in Single Institution. Ann. Oncol. 2013, 24, ix44. [Google Scholar] [CrossRef]
  41. Heon, S.; Nishino, M.; Goldberg, S.B.; Porter, J.; Sequist, L.V.; Jackman, D.M.; Johnson, B.E. Response to EGFR tyrosine kinase inhibitor (TKI) retreatment after a drug-free interval in EGFR-mutant advanced non-small cell lung cancer (NSCLC) with acquired resistance. J. Clin. Oncol. 2012, 30, 7525. [Google Scholar] [CrossRef]
  42. Chi, C.-Y.; Chiang, C.-L.; Chen, Y.-M.; Luo, Y.-H. EP08.02-134 Real-world Efficacy of Dacomitinib in Patients with Previously EGFR-TKI Treated Non-small Cell Lung Cancer. J. Thorac. Oncol. 2022, 17, S467. [Google Scholar] [CrossRef]
  43. Yamaguchi, O.; Kaira, K.; Mouri, A.; Shiono, A.; Hashimoto, K.; Miura, Y.; Nishihara, F.; Murayama, Y.; Kobayashi, K.; Kagamu, H. Re-challenge of afatinib after 1st generation EGFR-TKI failure in patients with previously treated non-small cell lung cancer harboring EGFR mutation. Cancer Chemother. Pharmacol. 2019, 83, 817–825. [Google Scholar] [CrossRef] [PubMed]
  44. Zhao, Z.-R.; Wang, J.-F.; Lin, Y.-B.; Wang, F.; Fu, S.; Zhang, S.-L.; Su, X.-D.; Jiang, L.; Zhang, Y.-G.; Shao, J.-Y.; et al. Mutation abundance affects the efficacy of EGFR tyrosine kinase inhibitor readministration in non-small-cell lung cancer with acquired resistance. Med. Oncol. 2013, 31, 810. [Google Scholar] [CrossRef] [PubMed]
  45. Araki, T.; Kanda, S.; Obara, M.; Agatsuma, T.; Kakizaki, Y.; Hama, M.; Yamamoto, H.; Takada, M.; Yamamoto, M.; Matsuo, A.; et al. EGFR-TKI rechallenge in patients with EGFR-mutated non-small-cell lung cancer who progressed after first-line osimertinib treatment: A multicenter retrospective observational study. Respir. Investig. 2024, 62, 262–268. [Google Scholar] [CrossRef] [PubMed]
  46. Yokouchi, H.; Yamazaki, K.; Kinoshita, I.; Konishi, J.; Asahina, H.; Sukoh, N.; Harada, M.; Akie, K.; Ogura, S.; Ishida, T.; et al. Clinical benefit of readministration of gefitinib for initial gefitinib-responders with non-small cell lung cancer. BMC Cancer 2007, 7, 51. [Google Scholar] [CrossRef] [PubMed]
  47. Yamada, Y.; Imai, H.; Sugiyama, T.; Minemura, H.; Kanazawa, K.; Kasai, T.; Minato, K.; Kaira, K.; Kaburagi, T. Effectiveness and Safety of EGFR-TKI Rechallenge Treatment in Elderly Patients with Advanced Non-Small-Cell Lung Cancer Harboring Drug-Sensitive EGFR Mutations. Medicina 2021, 57, 929. [Google Scholar] [CrossRef] [PubMed]
  48. Watanabe, S.; Tanaka, J.; Ota, T.; Kondo, R.; Tanaka, H.; Kagamu, H.; Ichikawa, K.; Koshio, J.; Baba, J.; Miyabayashi, T.; et al. Clinical responses to EGFR-tyrosine kinase inhibitor retreatment in non-small cell lung cancer patients who benefited from prior effective gefitinib therapy: A retrospective analysis. BMC Cancer 2011, 11, 1. [Google Scholar] [CrossRef] [PubMed]
  49. Tang, C.; Gao, H.; Li, X.; Liu, Y.; Li, J.; Qin, H.; Wang, W.; Qu, L.; An, J.; Yang, S.; et al. Different treatment orders achieved similar clinical results: A retrospective study for retreatment of epidermal growth factor receptor tyrosine kinase inhibitors in 120 patients with non-small-cell lung cancer. J. Cancer Res. Clin. Oncol. 2014, 140, 427–433. [Google Scholar] [CrossRef]
  50. Tanaka, H.; Taima, K.; Itoga, M.; Ishioka, Y.; Baba, K.; Shiratori, T.; Sakamoto, H.; Tsuchiya, J.; Nakagawa, H.; Hasegawa, Y.; et al. Real-world study of afatinib in first-line or re-challenge settings for patients with EGFR mutant non-small cell lung cancer. Med. Oncol. 2019, 36, 57. [Google Scholar] [CrossRef]
  51. Tanaka, H.; Sakamoto, H.; Akita, T.; Ohyanagi, F.; Kawashima, Y.; Tambo, Y.; Tanimoto, A.; Horiike, A.; Miyauchi, E.; Tsuchiya-Kawano, Y.; et al. Clinical efficacy of dacomitinib in rechallenge setting for patients with epidermal growth factor receptor mutant non–small cell lung cancer: A multicenter retrospective analysis (TOPGAN2020-02). Thorac. Cancer 2022, 13, 1471–1478. [Google Scholar] [CrossRef] [PubMed]
  52. Kwon, B.S.; Park, J.H.; Kim, W.S.; Song, J.S.; Choi, C.-M.; Rho, J.K.; Lee, J.C. Predictive Factors for Switched EGFR-TKI Retreatment in Patients with EGFR-Mutant Non-Small Cell Lung Cancer. Tuberc. Respir. Dis. 2017, 80, 187–193. [Google Scholar] [CrossRef] [PubMed]
  53. Cho, K.M.; Keam, B.; Kim, T.M.; Lee, S.-H.; Kim, D.-W.; Heo, D.S. Clinical efficacy of erlotinib, a salvage treatment for non-small cell lung cancer patients following gefitinib failure. Korean J. Intern. Med. 2015, 30, 891–898. [Google Scholar] [CrossRef] [PubMed]
  54. Han, J.-Y.; Lee, K.H.; Kim, S.-W.; Min, Y.J.; Cho, E.; Lee, Y.; Lee, S.-H.; Kim, H.Y.; Lee, G.K.; Nam, B.H.; et al. A Phase II Study of Poziotinib in Patients with Epidermal Growth Factor Receptor (EGFR)-Mutant Lung Adenocarcinoma Who Have Acquired Resistance to EGFR–Tyrosine Kinase Inhibitors. Cancer Res. Treat. 2017, 49, 10–19. [Google Scholar] [CrossRef] [PubMed]
  55. Miyawaki, T.; Kenmotsu, H.; Yabe, M.; Kodama, H.; Nishioka, N.; Miyawaki, E.; Mamesaya, N.; Kobayashi, H.; Omori, S.; Wakuda, K.; et al. Rechallenge with previously administered epidermal growth factor receptor-tyrosine kinase inhibitors in EGFR-mutated non-small cell lung cancer with leptomeningeal metastasis. Investig. New Drugs 2021, 39, 1732–1741. [Google Scholar] [CrossRef] [PubMed]
  56. Vavalà, T.; Follador, A.; Tiseo, M.; Galetta, D.; Morabito, A.; Di Maio, M.; Martelli, O.; Caffo, O.; Piovano, P.L.; Cortinovis, D.; et al. BE-POSITIVE: Beyond progression after tyrosine kinase inhibitor in EGFR- positive non small cell lung cancer patients. Lung Cancer 2016, 95, 73–81. [Google Scholar] [CrossRef] [PubMed]
  57. Takahashi, K.; Ito, K.; Murotani, K.; Asada, K.; Okuno, M.; Kimura, T.; Kubo, A.; Suda, T.; Taniguchi, H.; Hataji, O.; et al. P2.14-11 Retreatment with EGFR-TKI for 541 NSCLC Patients with EGFR Mutation. J. Thorac. Oncol. 2019, 14, S833. [Google Scholar] [CrossRef]
  58. Yoshino, R.; Tomizawa, Y.; Takei, K.; Kuwako, T.; Yoshii, A.; Watanabe, S.; Saitou, R. Retrospective Analysis of Re-Challenge of EGFR TK-IS in Patients with Advanced and Recurrent Non-Small Cell Lung Cancer. Ann. Oncol. 2013, 24, ix96. [Google Scholar] [CrossRef]
  59. Sun, L.; Tu, L.; Wei, M. 466P Gefitinib retreatment beyond progression in advanced NSCLC patients with sensitive EGFR mutations. Ann. Oncol. 2016, 27, ix149. [Google Scholar] [CrossRef]
  60. Sakamori, Y.; Yasuda, Y.; Funazo, T.; Nomizo, T.; Tsuji, T.; Yoshida, H.; Nagai, H.; Ozasa, H.; Hirai, T.; Kim, Y. P2.03-055 Comparison of Afatinib Versus Erlotinib for Advanced Non-Small-Cell Lung Cancer Patients with Resistance to EGFR-TKI. J. Thorac. Oncol. 2017, 12, S2396. [Google Scholar] [CrossRef]
  61. Ma, D.; Xing, P.; Li, J. P2.03-004 Recurrent Response to Advanced NSCLC with Erlotinib Developing Central Nervous System Failure during Gefitinib or Icotinib Treatment. J. Thorac. Oncol. 2017, 12, S2128–S2129. [Google Scholar] [CrossRef]
  62. Acharya, S. P48.14 Metastatic NSCLC -Re-Challenging with Fist Generation TKI After a Drug Free Holiday After Resistance to 3rd Generation TKI. J. Thorac. Oncol. 2021, 16, S1111–S1112. [Google Scholar] [CrossRef]
  63. Oda, N.; Ichihara, E.; Hotta, K.; Ninomiya, K.; Ninomiya, T.; Kubo, T.; Minami, D.; Murakami, T.; Yokoyama, T.; Harada, D.; et al. Phase II Study of the EGFR-TKI Rechallenge with Afatinib in Patients with Advanced NSCLC Harboring Sensitive EGFR Mutation without T790M: Okayama Lung Cancer Study Group Trial OLCSG 1403. Clin. Lung Cancer 2017, 18, 241–244. [Google Scholar] [CrossRef] [PubMed]
  64. Kodama, H.; Wakuda, K.; Yabe, M.; Nishioka, N.; Miyawaki, E.; Miyawaki, T.; Mamesaya, N.; Kawamura, T.; Kobayashi, H.; Omori, S.; et al. Retrospective analysis of osimertinib re-challenge after osimertinib-induced interstitial lung disease in patients with EGFR-mutant non-small cell lung carcinoma. Investig. New Drugs 2020, 39, 571–577. [Google Scholar] [CrossRef]
  65. Kuiper, J.L.; Heideman, D.A.; Würdinger, T.; Grünberg, K.; Groen, H.J.; Smit, E.F. Rationale and Study Design of the IRENE-Trial (NVALT-16): A Phase II Trial to Evaluate Iressa Rechallenge in Advanced NSCLC Patients with an Activating EGFR Mutation Who Responded to an EGFR-TKI Used As First-Line or Previous Treatment. Clin. Lung Cancer 2015, 16, 60–66. [Google Scholar] [CrossRef] [PubMed]
  66. Imaji, M.; Fujimoto, D.; Sato, Y.; Sakata, Y.; Oya, Y.; Tamiya, M.; Suzuki, H.; Ikeda, H.; Kijima, T.; Matsumoto, H.; et al. Safety and efficacy of osimertinib rechallenge or continuation after pneumonitis: A multicentre retrospective cohort study. Eur. J. Cancer 2023, 179, 15–24. [Google Scholar] [CrossRef]
  67. Araki, T.; Kanda, S.; Komatsu, M.; Sonehara, K.; Tateishi, K.; Takada, M.; Kato, A.; Yamamoto, M.; Nishie, K.; Hama, M.; et al. Rechallenge of afatinib for EGFR-mutated non-small cell lung cancer previously treated with osimertinib: A multicenter phase II trial protocol (REAL study). Transl. Lung Cancer Res. 2023, 12, 1320–1327. [Google Scholar] [CrossRef]
  68. Marrett, E.; Kwong, W.J.; Xie, J.; Manceur, A.M.; Sendhil, S.R.; Wu, E.; Ionescu-Ittu, R.; Subramanian, J. Treatment Patterns and Adverse Event-Related Hospitalization Among Patients with Epidermal Growth Factor Receptor (EGFR)-Mutated Metastatic Non-small Cell Lung Cancer After Treatment with EGFR Tyrosine Kinase Inhibitor and Platinum-Based Chemotherapy Regimens. Drugs-Real World Outcomes 2023, 10, 531–544. [Google Scholar] [CrossRef] [PubMed]
  69. Guo, M.; Vanderwalde, A.M.; Yu, X.; Vidal, G.A.; Tian, G.G. The safety and efficacy of immune checkpoint inhibitor rechallenge after immune-related adverse events in stage IV NSCLC patients. J. Clin. Oncol. 2022, 40, e21173. [Google Scholar] [CrossRef]
  70. Maemondo, M.; Inoue, A.; Kobayashi, K.; Sugawara, S.; Oizumi, S.; Isobe, H.; Gemma, A.; Harada, M.; Yoshizawa, H.; Kinoshita, I.; et al. Gefitinib or Chemotherapy for Non–Small-Cell Lung Cancer with Mutated EGFR. N. Engl. J. Med. 2010, 362, 2380–2388. [Google Scholar] [CrossRef]
  71. Mitsudomi, T.; Morita, S.; Yatabe, Y.; Negoro, S.; Okamoto, I.; Tsurutani, J.; Seto, T.; Satouchi, M.; Tada, H.; Hirashima, T.; et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial. Lancet Oncol. 2010, 11, 121–128. [Google Scholar] [CrossRef] [PubMed]
  72. Wu, Y.-L.; Zhou, C.; Hu, C.-P.; Feng, J.; Lu, S.; Huang, Y.; Li, W.; Hou, M.; Shi, J.H.; Lee, K.Y.; et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): An open-label, randomised phase 3 trial. Lancet Oncol. 2014, 15, 213–222. [Google Scholar] [CrossRef] [PubMed]
  73. Kim, S.Y.; Myung, J.K.; Kim, H.-R.; Na, I.I.; Koh, J.S.; Baek, H.J.; Kim, C.H. Factors that Predict Clinical Benefit of EGFR TKI Therapy in Patients with EGFR Wild-Type Lung Adenocarcinoma. Tuberc. Respir. Dis. 2019, 82, 62. [Google Scholar] [CrossRef] [PubMed]
  74. Wang, F.; Fu, S.; Shao, Q.; Zhou, Y.-B.; Zhang, X.; Zhang, X.; Xue, C.; Lin, J.-G.; Huang, L.-X.; Zhang, L.; et al. High EGFR copy number predicts benefits from tyrosine kinase inhibitor treatment for non-small cell lung cancer patients with wild-type EGFR. J. Transl. Med. 2013, 11, 90. [Google Scholar] [CrossRef] [PubMed]
  75. Smith, M.R.; Wang, Y.; D’Agostino, R.; Liu, Y.; Ruiz, J.; Lycan, T.; Oliver, G.; Miller, L.D.; Topaloglu, U.; Pinkney, J.; et al. Prognostic Mutational Signatures of NSCLC Patients treated with chemotherapy, immunotherapy and chemoimmunotherapy. NPJ Precis. Onc. 2023, 7, 34. [Google Scholar] [CrossRef] [PubMed]
  76. Westover, D.; Zugazagoitia, J.; Cho, B.C.; Lovly, C.M.; Paz-Ares, L. Mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors. Ann. Oncol. 2018, 29, i10–i19. [Google Scholar] [CrossRef] [PubMed]
  77. Dogan, I.; Khanmammadov, N.; Yıldız, A.; Ahmed, M.A.; Vatansever, S.; Saip, P.; Aydiner, A. Predictors of response in EGFR-mutant metastatic non-small cell lung cancer patients treated with tyrosine kinase inhibitors. J. Cancer Res. Ther. 2023, 19, 1945–1949. [Google Scholar] [CrossRef] [PubMed]
  78. Patel, K.H.; Alpert, N.; Tuminello, S.; Taioli, E. Personal and clinical characteristics associated with immunotherapy effectiveness in stage IV non-small cell lung cancer. Transl. Lung Cancer Res. 2023, 12, 1210–1220. [Google Scholar] [CrossRef]
  79. Huang, L.; Li, L.; Zhou, Y.; Yang, Z.; Wang, M.; Gao, Y.; Yang, Y.; Yang, F.; Liu, B.; Hong, X.; et al. Clinical Characteristics Correlate with Outcomes of Immunotherapy in Advanced Non-Small Cell Lung Cancer. J. Cancer 2020, 11, 7137–7145. [Google Scholar] [CrossRef]
  80. Wagener-Ryczek, S.; Heydt, C.; Süptitz, J.; Michels, S.; Falk, M.; Alidousty, C.; Fassunke, J.; Ihle, M.A.; Tiemann, M.; Heukamp, L.; et al. Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors. BMC Cancer 2020, 20, 408. [Google Scholar] [CrossRef]
  81. Gazdar, A.F. Activating and resistance mutations of EGFR in non-small-cell lung cancer: Role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene 2009, 28, S24–S31. [Google Scholar] [CrossRef] [PubMed]
  82. Gao, X.; Zhao, Y.; Bao, Y.; Yin, W.; Liu, L.; Liu, R.; Yu, Z.; Zhou, X.; Shuai, J. Poor Prognosis with Coexistence Of EGFR T790M Mutation And Common EGFR-Activating Mutation In Non- Small Cell Lung Cancer. CMAR 2019, 11, 9621–9630. [Google Scholar] [CrossRef] [PubMed]
  83. Grassberger, C.; McClatchy, D.; Geng, C.; Kamran, S.C.; Fintelmann, F.; Maruvka, Y.E.; Piotrowska, Z.; Willers, H.; Sequist, L.V.; Hata, A.N.; et al. Patient-Specific Tumor Growth Trajectories Determine Persistent and Resistant Cancer Cell Populations during Treatment with Targeted Therapies. Cancer Res. 2019, 79, 3776–3788. [Google Scholar] [CrossRef] [PubMed]
  84. Weinstein, I.B.; Joe, A.K. Mechanisms of Disease: Oncogene addiction—A rationale for molecular targeting in cancer therapy. Nat. Rev. Clin. Oncol. 2006, 3, 448–457. [Google Scholar] [CrossRef] [PubMed]
  85. Nardin, C.; Hennemann, A.; Diallo, K.; Funck-Brentano, E.; Puzenat, E.; Heidelberger, V.; Jeudy, G.; Samimi, M.; Lesage, C.; Boussemart, L.; et al. Efficacy of immune checkpoint inhibitor (ICI) rechallenge in advanced melanoma patients responders to a first course of ICI: A multicenter, national, retrospective study of the French group of skin cancers (GCC). JCO 2022, 40, 9529. [Google Scholar] [CrossRef]
  86. Suwaidan, A.A.; Zhang, S.; Faust, G. The efficacy and safety of rechallenge with an alternative immune checkpoint inhibitor in metastatic malignant melanoma. Ann. Oncol. 2018, 29, x19–x20. [Google Scholar] [CrossRef]
  87. Cremolini, C.; Montagut, C.; Ronga, P.; Venturini, F.; Yamaguchi, K.; Stintzing, S.; Sobrero, A. Rechallenge with anti-EGFR therapy to extend the continuum of care in patients with metastatic colorectal cancer. Front. Oncol. 2023, 12, 946850. [Google Scholar] [CrossRef] [PubMed]
  88. Hu, H.; Wang, K.; Jia, R.; Zeng, Z.-X.; Zhu, M.; Deng, Y.-L.; Xiong, Z.-J.; Tang, J.-N.; Xie, H.; Wang, Y.; et al. Current Status in Rechallenge of Immunotherapy. Int. J. Biol. Sci. 2023, 19, 2428–2442. [Google Scholar] [CrossRef] [PubMed]
  89. Hanovich, E.; Asmis, T.; Ong, M.; Stewart, D. Rechallenge Strategy in Cancer Therapy. Oncology 2020, 98, 669–679. [Google Scholar] [CrossRef]
  90. Kuczynski, E.A.; Sargent, D.J.; Grothey, A.; Kerbel, R.S. Drug rechallenge and treatment beyond progression-implications for drug resistance. Nat. Rev. Clin. Oncol. 2013, 10, 571–587. [Google Scholar] [CrossRef]
  91. Priantti, J.N.; Vilbert, M.; Madeira, T.; Moraes, F.C.A.; Hein, E.C.K.; Saeed, A.; Cavalcante, L. Efficacy and Safety of Rechallenge with BRAF/MEK Inhibitors in Advanced Melanoma Patients: A Systematic Review and Meta-Analysis. Cancers 2023, 15, 3754. [Google Scholar] [CrossRef]
  92. Koulouris, A.; Tsagkaris, C.; Corriero, A.C.; Metro, G.; Mountzios, G. Resistance to TKIs in EGFR-Mutated Non-Small Cell Lung Cancer: From Mechanisms to New Therapeutic Strategies. Cancers 2022, 14, 3337. [Google Scholar] [CrossRef]
  93. Chhouri, H.; Alexandre, D.; Grumolato, L. Mechanisms of Acquired Resistance and Tolerance to EGFR Targeted Therapy in Non-Small Cell Lung Cancer. Cancers 2023, 15, 504. [Google Scholar] [CrossRef]
  94. Leonetti, A.; Sharma, S.; Minari, R.; Perego, P.; Giovannetti, E.; Tiseo, M. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br. J. Cancer 2019, 121, 725–737. [Google Scholar] [CrossRef]
  95. Morgillo, F.; Della Corte, C.M.; Fasano, M.; Ciardiello, F. Mechanisms of resistance to EGFR-targeted drugs: Lung cancer. ESMO Open 2016, 1, e000060. [Google Scholar] [CrossRef]
  96. Zhong, W.-Z.; Zhou, Q.; Wu, Y.-L. The resistance mechanisms and treatment strategies for EGFR -mutant advanced non-small-cell lung cancer. Oncotarget 2017, 8, 71358–71370. [Google Scholar] [CrossRef]
  97. Wu, S.-G.; Shih, J.-Y. Management of acquired resistance to EGFR TKI–targeted therapy in advanced non-small cell lung cancer. Mol. Cancer 2018, 17, 38. [Google Scholar] [CrossRef]
  98. Guo, H.; Zhang, J.; Qin, C.; Yan, H.; Liu, T.; Hu, H.; Tang, S.; Tang, S.; Zhou, H. Biomarker-Targeted Therapies in Non-Small Cell Lung Cancer: Current Status and Perspectives. Cells 2022, 11, 3200. [Google Scholar] [CrossRef]
  99. Yu, H.A.; Goldberg, S.B.; Le, X.; Piotrowska, Z.; Goldman, J.W.; De Langen, A.J.; Okamoto, I.; Cho, B.C.; Smith, P.; Mensi, I.; et al. Biomarker-Directed Phase II Platform Study in Patients with EGFR Sensitizing Mutation-Positive Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib Therapy (ORCHARD). Clin. Lung Cancer 2021, 22, 601–606. [Google Scholar] [CrossRef] [PubMed]
  100. Passaro, A.; Wang, J.; Wang, Y.; Lee, S.-H.; Melosky, B.; Shih, J.-Y.; Wang, J.; Azuma, K.; Juan-Vidal, O.; Cobo, M.; et al. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: Primary results from the phase III MARIPOSA-2 study. Ann. Oncol. 2024, 35, 77–90. [Google Scholar] [CrossRef] [PubMed]
  101. Mu, Y.; Hao, X.; Yang, K.; Ma, D.; Wang, S.; Xu, Z.; Li, J.; Xing, P. Clinical Modality of Resistance and Subsequent Management of Patients with Advanced Non-small Cell Lung Cancer Failing Treatment with Osimertinib. Targ. Oncol. 2019, 14, 335–342. [Google Scholar] [CrossRef]
  102. Le, X.; Puri, S.; Negrao, M.V.; Nilsson, M.B.; Robichaux, J.; Boyle, T.; Hicks, J.K.; Lovinger, K.L.; Roarty, E.; Rinsurongkawong, W.; et al. Landscape of EGFR-Dependent and -Independent Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in EGFR -Mutant NSCLC. Clin. Cancer Res. 2018, 24, 6195–6203. [Google Scholar] [CrossRef]
  103. Goulart, B.H.L.; Larkins, E.; Beaver, J.A.; Singh, H. Continuation of Third-Generation Tyrosine Kinase Inhibitors in Second-Line Trials for EGFR -Mutated Non-Small-Cell Lung Cancer: Regulatory Considerations. JCO 2023, 41, 3905–3908. [Google Scholar] [CrossRef]
  104. Yu, H.A.; Goto, Y.; Hayashi, H.; Felip, E.; Chih-Hsin Yang, J.; Reck, M.; Yoh, K.; Lee, S.-H.; Paz-Ares, L.; Besse, B.; et al. HERTHENA-Lung01, a Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in Epidermal Growth Factor Receptor–Mutated Non–Small-Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Platinum-Based Chemotherapy. JCO 2023, 41, 5363–5375. [Google Scholar] [CrossRef]
  105. Kurtovic-Kozaric, A.; Vranic, S.; Kurtovic, S.; Hasic, A.; Kozaric, M.; Granov, N.; Ceric, T. Lack of Access to Targeted Cancer Treatment Modalities in the Developing World in the Era of Precision Medicine: Real-Life Lessons from Bosnia. JGO 2018, 4, 1–5. [Google Scholar] [CrossRef]
  106. Pramesh, C.S.; Badwe, R.A.; Bhoo-Pathy, N.; Booth, C.M.; Chinnaswamy, G.; Dare, A.J.; De Andrade, V.P.; Hunter, D.J.; Gopal, S.; Gospodarowicz, M.; et al. Priorities for cancer research in low- and middle-income countries: A global perspective. Nat. Med. 2022, 28, 649–657. [Google Scholar] [CrossRef]
  107. Mallath, M.K.; Taylor, D.G.; Badwe, R.A.; Rath, G.K.; Shanta, V.; Pramesh, C.S.; Digumarti, R.; Sebastian, P.; Borthakur, B.B.; Kalwar, A.; et al. The growing burden of cancer in India: Epidemiology and social context. Lancet Oncol. 2014, 15, e205–e212. [Google Scholar] [CrossRef]
  108. Surapaneni, M.; Uprety, D. Lung cancer management in low and middle-income countries—Current challenges and potential solutions. Int. J. Cancer Care Deliv. 2023, 3. [Google Scholar] [CrossRef]
  109. Barrios, C.; De Lima Lopes, G.; Yusof, M.M.; Rubagumya, F.; Rutkowski, P.; Sengar, M. Barriers in access to oncology drugs—A global crisis. Nat. Rev. Clin. Oncol. 2023, 20, 7–15. [Google Scholar] [CrossRef]
Jpm 14 00752 g001
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flow diagram of study screening and selection. Blue vertical boxes indicate each stage of the screening, and the horizontal boxes present more detailed information about the process, including the steps performed in each stage. ASCO: American Society of Clinical Oncology; ESMO: European Society for Medical Oncology.
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flow diagram of study screening and selection. Blue vertical boxes indicate each stage of the screening, and the horizontal boxes present more detailed information about the process, including the steps performed in each stage. ASCO: American Society of Clinical Oncology; ESMO: European Society for Medical Oncology.
Jpm 14 00752 g001
Jpm 14 00752 g002
Figure 2. Median OS in patients rechallenged with first/second-generation TKI (A), and PFS according to the TKI generation used in the rechallenge period (B) [17,18,19,21,22,25,26,28,32,33,33]. Proportions for each trial are represented by a square, and the horizontal line crossing the squares indicates the 95% confidence interval. The diamonds represent the estimated overall effect of the meta-analysis based on random effects. CI: confidence interval; m: median; OS: overall survival; PFS: progression-free survival; TKI: tyrosine kinase inhibitor; SE: standard error. Kaira (B) refers to patients who did not receive PD-1 blockade before rechallenging [21].
Figure 2. Median OS in patients rechallenged with first/second-generation TKI (A), and PFS according to the TKI generation used in the rechallenge period (B) [17,18,19,21,22,25,26,28,32,33,33]. Proportions for each trial are represented by a square, and the horizontal line crossing the squares indicates the 95% confidence interval. The diamonds represent the estimated overall effect of the meta-analysis based on random effects. CI: confidence interval; m: median; OS: overall survival; PFS: progression-free survival; TKI: tyrosine kinase inhibitor; SE: standard error. Kaira (B) refers to patients who did not receive PD-1 blockade before rechallenging [21].
Jpm 14 00752 g002
Jpm 14 00752 g003
Figure 3. Objective response rate (ORR) according to the studies’ designs (A); ORR according to mutational status (B); ORR according to generation of TKI used in rechallenge (C); and ORR according to TKI drug pattern used in rechallenge (same vs. different TKI) (D) [17,18,19,20,21,22,25,26,28,29,30,31,32,33,34,35,36,37]. Proportions for each trial are represented by a square and the horizontal line crossing the squares indicates the 95% confidence interval. The diamonds represent the estimated overall effect of the meta-analysis based on random effects. CI: confidence interval; TKI: tyrosine kinase inhibitor. In Becker 2011, only one patient was treated with gefitinib and then erlotinib; all the others were first exposed to erlotinib both in the first-line treatment and rechallenge. Kaira (A): refers to patients treated with PD-1 blockade before TKI rechallenge; Kaira (B) refers to patients who did not receive PD-1 blockade before rechallenging [21].
Figure 3. Objective response rate (ORR) according to the studies’ designs (A); ORR according to mutational status (B); ORR according to generation of TKI used in rechallenge (C); and ORR according to TKI drug pattern used in rechallenge (same vs. different TKI) (D) [17,18,19,20,21,22,25,26,28,29,30,31,32,33,34,35,36,37]. Proportions for each trial are represented by a square and the horizontal line crossing the squares indicates the 95% confidence interval. The diamonds represent the estimated overall effect of the meta-analysis based on random effects. CI: confidence interval; TKI: tyrosine kinase inhibitor. In Becker 2011, only one patient was treated with gefitinib and then erlotinib; all the others were first exposed to erlotinib both in the first-line treatment and rechallenge. Kaira (A): refers to patients treated with PD-1 blockade before TKI rechallenge; Kaira (B) refers to patients who did not receive PD-1 blockade before rechallenging [21].
Jpm 14 00752 g003
Jpm 14 00752 g004
Figure 4. Disease control rate (DCR) according to studies´design (A); DCR according to mutational status (B); DCR according to generation of TKI used in rechallenge (C); and DCR according to TKI drug pattern used in rechallenge (same vs. different TKI) (D) [17,18,19,20,21,22,25,26,28,29,30,31,32,33,34,35,36,37]. Proportions for each trial are represented by a square and the horizontal line crossing the squares indicates the 95% confidence interval. The diamonds represent the estimated overall effect of the meta-analysis based on random effects. CI: confidence interval; TKI: tyrosine kinase inhibitors. In Becker 2011 only one patient was treated with gefitinib and then erlotinib, all the others were first exposed to erlotinib both in the first-line treatment and rechallenge. Kaira (A): refers to patients treated with PD-1 blockade before TKI rechallenge; Kaira (B) refers to patients who did not receive PD-1 blockade before rechallenging [21].
Figure 4. Disease control rate (DCR) according to studies´design (A); DCR according to mutational status (B); DCR according to generation of TKI used in rechallenge (C); and DCR according to TKI drug pattern used in rechallenge (same vs. different TKI) (D) [17,18,19,20,21,22,25,26,28,29,30,31,32,33,34,35,36,37]. Proportions for each trial are represented by a square and the horizontal line crossing the squares indicates the 95% confidence interval. The diamonds represent the estimated overall effect of the meta-analysis based on random effects. CI: confidence interval; TKI: tyrosine kinase inhibitors. In Becker 2011 only one patient was treated with gefitinib and then erlotinib, all the others were first exposed to erlotinib both in the first-line treatment and rechallenge. Kaira (A): refers to patients treated with PD-1 blockade before TKI rechallenge; Kaira (B) refers to patients who did not receive PD-1 blockade before rechallenging [21].
Jpm 14 00752 g004
Table 1. Design and characteristics of studies included in the meta-analysis.
Table 1. Design and characteristics of studies included in the meta-analysis.
StudyDesignLocationNFemale
N (%)		Median
Age in Years (Range)		Non-Smokers
N (%)		ECOG PS
N (%)		Initial
TKI		Rechallenge
TKI		Rechallenge
Line of Treatment
N (%)		TKI-Free Interval
in Months a		Median Follow-Up
Interval in Months
(Range)
0–1≥23rd≥4th
Asahina
2010 [25]		Phase II CTJapan1613 (81)66.5 (53–79)11 (69)14 (87.5)2 (12.5)GefGef2 (12.5)14 (87.5)≤6 mos: 8 (50)
6–12 mos: 6 (38)
≥12 mos: 2 (13) b		14.7
Becker
2011 [26]		Retrospective cohortNetherlands149 (64)55 (39–70)NANANAErl cErl c14 (100)09.5 (3–36)9 (1.5–16+)
Cappuzzo
2016 [12]		Phase II CTItaly6145 (73.8)67 (40–86)41 (67.2) d50 (82)10 (8) eGefGef61 (100)0NA9 (0–19)
Chang
2017 [22]		Retrospective cohortTaiwan205129 (62.9)61.8 (31.4–92.9)150 (73.2) d34171Gef, Erl,
Afa		Gef, Erl,
Afa		205 (100)0NANA
Chen
2016 [27]		Retrospective cohortTaiwan80NANANANANANANANANA<3 mos: 16 (20)
3–6 mos: 25 (31.3)
>6 mos: 39 (48.8) b		7 (NA)
Ichihara
2019 [20]		Retrospective cohortJapan1711 (65.7)68 (43–78)17 (100)116OsiOsiNANA f5.9 (0.6–19)NA
Kaira
2021 [21]		Retrospective cohortJapan7546 (61.3)65 (39–79)43 (57.3)56 (74.7)19 (25.3)Gef, Erl,
Afa, Osi		Gef, Erl,
Afa		13 (17.3)62 (82.7)NANA
Koizumi
2012 [28]		Phase II CTJapan2017 (85)61 (41–81)18 (90) d14 (70)6 (30)GefGef3 (15)17 (85)NANA
Y. Lee 2023 [29] *Phase II CTSouth Korea63NA65 (NA)NANANAGef, ErlGef, ErlNANANANA
Lee
2014 [30]		Retrospective cohortSouth Korea6854 (79.4)NA57 (83.8) d34 (50)34 (50)Gef, ErlGef, Erl68 (100)09.8 (2.1–22.4)38.9 (34.7–44.5)
Oda
2018 [19]		Phase II CTJapan129 (75)67.5 (52–86)1 (8.3) d12 (100)0Gef,
Erl, Afa		AfaNANA g9.6 (2.5–37.8) 10.2 (4.3–31.9)
Oh
2012 [32]		Phase II CTSouth Korea2320 (86.9)65 (45–79)21 (91.3) d17 (73.9)6 (26)GefGef023 (100)7 (2.5–25)8.6 (0.4–20.8)
Song
2019 [17]		Phase II CTChina4330 (69.8)57 (46–77)36 (83.7)37 (86)6 (14)GefGef43 (100)0NANA
Song
2013 [33]		Retrospective cohortChina3317 (51.5)57.9 (32–76)23 (69.7)22 (66.6)11 (33.4)Erl, GefErl, Gef33 (100)0NA30.2 (6.7–56)
Soto Parra
2021 [35] *		Phase II CTItaly5437 (68.5)NANA54 (100)0OsiOsi54 (100)0NANA
Tomizawa
2009 [34]		Retrospective cohortJapan2017 (85)67 (34–79)15 (75)18 (90)2 (10)GefGefNANA7.2 (1.4–27.3)NA
Uy
2023 [31] *		Retrospective cohortUnited States1711 (65)62 (42–73)13 (77)12 (70.6)5 (29.4)Erl, Afa, OsiOsiNANA h13.8 (3.2–50.7)NA
Xia
2014 [36]		Phase II CTChina2712 (44.4)NA24 (88.9) d20 (74)7 (26)Gef, Erl,
Ico		Gef, Erl,
Ico		27 (100)0NANA
Yu
2013 [37]		Retrospective cohortChina3822 (57.9)Gef-group:54 (50.6–57.4)
Erl-group: 52 (42.2–61.8) 		28 (73.7)NANAGefGef, Erl38 (100)0Gef-group:4 (NA)
Erl-group: 5 (NA)		NA
Afa: afatinib; CT: clinical trial; ECOG PS: Eastern Cooperative Oncology Group Performance Status; Erl: erlotinib; Gef: gefitinib; Ico: icotinib; NA: not available; mos: months; N: number of patients; TKI: tyrosine kinase inhibitors; USA: United States of America; Osi: osimertinib; * abstracts from conferences. a: TKI-free interval is presented as median (range) unless indicated otherwise; b: in these studies, TKI-free interval was presented in three categories, followed by the number of patients in each category, and percentages are presented between parenthesis; c: in the study Becker 2011, most patients (13 out of 14) received erl in the initial and rechallenge treatment, alone or in combination with other agents, and only one patient received gef as the initial treatment and was rechallenged with erlotinib; d: never smokers; e: information about ECOG PS not available for one patient; f: in this study, the median number of previous therapies was five; g: in this study, the median number of therapies was four; h: in this study the median number of therapies was three.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Michelon, I.; Vilbert, M.; do Rego Castro, C.E.; Stecca, C.; Dacoregio, M.I.; Rizzo, M.; Cláudio Cordeiro de Lima, V.; Cavalcante, L. EGFR-Tyrosine Kinase Inhibitor Retreatment in Non-Small-Cell Lung Cancer Patients Previously Exposed to EGFR-TKI: A Systematic Review and Meta-Analysis. J. Pers. Med. 2024, 14, 752. https://doi.org/10.3390/jpm14070752

AMA Style

Michelon I, Vilbert M, do Rego Castro CE, Stecca C, Dacoregio MI, Rizzo M, Cláudio Cordeiro de Lima V, Cavalcante L. EGFR-Tyrosine Kinase Inhibitor Retreatment in Non-Small-Cell Lung Cancer Patients Previously Exposed to EGFR-TKI: A Systematic Review and Meta-Analysis. Journal of Personalized Medicine. 2024; 14(7):752. https://doi.org/10.3390/jpm14070752

Chicago/Turabian Style

Michelon, Isabella, Maysa Vilbert, Caio Ernesto do Rego Castro, Carlos Stecca, Maria Inez Dacoregio, Manglio Rizzo, Vladmir Cláudio Cordeiro de Lima, and Ludimila Cavalcante. 2024. "EGFR-Tyrosine Kinase Inhibitor Retreatment in Non-Small-Cell Lung Cancer Patients Previously Exposed to EGFR-TKI: A Systematic Review and Meta-Analysis" Journal of Personalized Medicine 14, no. 7: 752. https://doi.org/10.3390/jpm14070752

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop