Cancer Treatment Reviews 126 (2024) 102724

Contents lists available at ScienceDirect

Cancer Treatment Reviews

journal homepage: www.elsevier.com/locate/ctrv

Neoadjuvant EGFR-TKI therapy in Non-Small cell lung cancer

Christopher Grant a, Misako Nagasaka a, b, *
a
Department of Medicine, University of California Irvine Medical Center, Orange CA, USA
b
Division of Hematology and Oncology, Department of Medicine, University of California Irvine Medical Center, Orange CA, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Non-small cell lung cancer (NSCLC) stages I-III are predominantly treated with surgery and combination
Neoadjuvant targeted therapy immunotherapy and chemotherapy. A majority of these studies excluded patients with EGFR and ALK alterations.
Perioperative targeted therapy There are several completed and ongoing trials evaluating neoadjuvant treatment with EGFR-TKI monotherapy,
NEOADAURA
combination therapy with chemotherapy, and combination therapy with immunotherapy. Here, we review
EGFR-mutant
Osimertinib
completed clinical trials and discuss current ongoing trials’ potential benefits, challenges, and future directions in
the field.

Introduction tyrosine kinase inhibitor (TKI) preoperative treatment for EGFR-

mutated NSCLC [4] as Checkmate-816 itself had excluded those with
Lung cancer is the leading cause of cancer deaths worldwide attrib­ EGFR and ALK.
uting to 1.8 million deaths [1]. Surgical resection is the standard of care EGFR is a transmembrane receptor that links the ligand-binding
for resectable early-stage non-small cell lung carcinoma (NSCLC) [2]. domain to intracellular tyrosine kinase signaling domain, promoting
25–70 % of patients eventually develop a relapse after complete resec­ tyrosine phosphorylation and subsequently bronchial proliferation [9].
tion [3]. Neoadjuvant therapy is defined as any therapy delivered prior EGFR pro-oncogenic mutations have been genetically sequenced, and
to definitive surgical therapy intended to increase the cure rate [4]. include exon 19 deletions and exon 21 (L858R) mutations [10]. Tyrosine
Neoadjuvant therapy has many benefits in its potential to increase sur­ kinase inhibitors were created to inhibit tyrosine phosphorylation. The
vival. One of the biggest benefits is that it can provide prompt treatment first milestone EGFR-TKI study was Iressa Pan-Asia Study which was the
of subclinical micrometastasis before there is an opportunity to prolif­ first randomized clinical trial comparing an EGFR-TKI known as gefiti­
erate, creating a longer progression free survival and increasing the nib with chemotherapy. The study demonstrated a significant
chance of overall survival [5]. Additionally, downstaging of tumors can improvement in progression-free survival (PFS) of the EGFR-mutated
make tumors more operable, increasing the chance of performing patient population [11]. Several phase 3 studies led to gefitinib being
complete resection or an opportunity to utilize less invasive surgical the first TKI to be approved for first-line treatment of NSCLC patients
intervention [6]. While there are several benefits to neoadjuvant ther­ harboring an EGFR mutation in 2010 [12,13]. Erlotinib and icotinib
apy, some disadvantages exist including prolonged time a tumor re­ were later developed. Despite their success, a large number of patients
mains in the body, potential delays of surgical intervention due to developed acquired resistance within 9 to 14 months during or after
adverse events, and increased surgical complexity due to thoracic ad­ EGFR-TKI therapy with tumors harboring a T790M mutation [14]. Two
hesions and fibrosis [7]. second-generation EGFR-TKIs, afatinib and dacomitinib, were devel­
Checkmate-816 was groundbreaking in that it demonstrated how oped. The LUX-Lung 3 study was a phase III study evaluating afatinib in
combination neoadjuvant therapy with nivolumab and chemotherapy patients harboring EGFR mutations. It was found that PFS was 13.6
results in a significantly longer event-free survival and pathologic months for afatinib which was statistically significant compared to
complete response [8]. This finding dramatically changed the landscape chemotherapy [15]. Dacomitinib was compared against gefitinib in
of neoadjuvant treatment of NSCLC and provided the foundation for ARCHER 1050, which was a phase III trial in which dacomitinib
exploration of a variety of neoadjuvant treatment possibilities including demonstrated improved PFS over gefitinib in first-line treatment of pa­
targeted therapy and therefore epidermal growth factor receptor (EGFR) tients with EGFR-mutated NSCLC although the prevalence of treatment-

* Corresponding author at: Division of Hematology and Oncology, Department of Medicine, University of California Irvine Medical Center UC Irvine Health, 200 S
Manchester Ave, Room 423, Orange, CA 92868, USA.
E-mail address: nagasakm@hs.uci.edu (M. Nagasaka).

https://doi.org/10.1016/j.ctrv.2024.102724
Received 2 January 2024; Received in revised form 27 February 2024; Accepted 26 March 2024
Available online 27 March 2024
0305-7372/© 2024 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
C. Grant and M. Nagasaka Cancer Treatment Reviews 126 (2024) 102724

related adverse events was elevated compared to gefitinib [16]. small cell lung cancer”, “epidermal growth factor receptor”, “EGFR”,
Despite these advances, given the incidence of adverse events and “EGFR-mutant”, “neoadjuvant”, “tyrosine kinase inhibitors”, “TKIs”,
continued resistance, third-generation TKIs were created Osimertinib “lung cancer screening”, “ctDNA”, “circulating tumor DNA,” “molecular
was designed as the first third-generation EGFR-TKI approved by the mechanism resistance.” When evaluating ongoing clinical trials through
FDA, which irreversibly binds to cysteine at position 797 [17]. Through Clinicaltrials.gov, the following search terms were used: “NSCLC” and
a series of clinical trials assessing the safety profile of osimertinib as well “neoadjuvant.”. Data extracted included the name of the author, pub­
as the efficacy compared to both chemotherapy (AURA studies) and lication year, study characteristics, outcomes including overall response
first-generation EGFR-TKIs through the FLAURA trial, osimertinib was rate (ORR), progression free survival (PFS), disease free survival (DFS),
approved for treatment in the first line for metastatic or unresectable overall survival (OS), surgery resection rate (SRR), pathologic complete
EGFR exon 19 deletion or L858R [18]. response rate (pCR), major pathologic response rate (MPR), and adverse
The advent of EGFR-TKIs in the metastatic and unresectable setting events (AEs).
prompted clinical trials in the adjuvant setting. ADAURA was a double-
blind, phase III trial where 682 patients with completely resected EGFR Completed case reports and initial smaller studies using EGFR-
mutation-positive NSCLC were randomized to either receive osimertinib TKI monotherapy
or placebo for up to three years until progression or toxicity [19]. At 24
months, 90 % of patients with stage II to IIIA disease in the osimertinib One of the first case report using preoperative EGFR-TKI mono­
group (95 % CI 84 %-93 %) were alive and 44 % of those in the placebo therapy was published in 2008. Kappers et al. presented a 67-year-old
group (95 % CI 37 %-51 %). The overall survival showed that osi­ never-smoking women who had been found to have a stage III NSCLC
mertinib reduced the risk of death by 51 % with a hazard ratio of 0.49 with an EGFR exon 19 deletion [23]. She was given neoadjuvant erlo­
(95 % CI 0.33–0.73, P = 0.0004) [20]. Osimertinib has been FDA tinib 150 mg daily for 3 weeks with a subsequent anatomic resection of
approved as adjuvant therapy in patients with NSCLC whose tumors the apex of the left lower lobe with mediastinal lymph node dissection
have EGFR exon 19 deletions or exon 21 mutations [21]. Fig. 1 describes showed a near complete pathological response of locally advanced
the historical overview of EGFR-TKI treatment in the perioperative NSCLC. In 2012, a subsequent case report was published using neo­
period. adjuvant erlotinib 150 mg daily for 12 weeks on a female with a
The field of neoadjuvant EGFR-mutant targeted therapy is currently papillary adenocarcinoma of the lung with an EGFR point mutation
in the beginning stages and holds great promise [22]. Given the advent (L861Q) in exon 21 [24,25]. She had an uncomplicated right middle
of Checkmate-816, preoperative chemotherapy and immunotherapy lobe lobectomy in January 2010 continued erlotinib in the postoperative
resulted in significantly longer event-free survival without increasing period with a high quality of life and great response.
adverse events or impeding the feasibility of surgery [8]. Since An initial study was performed in the Netherlands to investigate the
Checkmate-816, preoperative targeted therapy clinical trials have safety of neoadjuvant erlotinib treatment in early-stage (T1-3 N0-1)
become increasingly prevalent due to the predicted benefits in efficacy, resectable NSCLC [26]. The study was performed on 15 patients denoted
necessitating an updated narrative review article to discuss the strengths as an enriched population (never-smoker, female, Asian ethnicity, and
and limitations of these clinical trials and provide a landscape of several non-squamous carcinoma) and 60 unselected patients. Individuals were
key inquiries shaping the EGFR-mutant NSCLC field. treated with erlotinib 150 mg daily for three weeks with subsequent
radical resection of the tumor, preferably by lobectomy. Metabolic
Methods partial response, measured by a positron electron tomography (PET)
scan, was seen in 10 patients from the enriched population and 6 un­
The review was conducted using databases including PubMed, selected patients. Toxicity was mild with 7 patients stopping treatment
Clinicaltrials.gov, and Google Scholar. Studies that were included con­ due to skin rashes. This data demonstrated the minimal toxicity and
sisted of initial case studies as well as prospective studies evaluating the highlighted how certain characteristics (such as those in the enriched
efficacy or safety of preoperative EGFR-TKI for resectable NSCLC with population) and EGFR-mutational status plays a role as a majority of the
an EGFR-sensitive mutation. The following search terms were used in individuals who had a response demonstrated an EGFR-mutation.
the literature search in PubMed and google scholar: “NSCLC”, “Non- A subsequent study by the University of Toronto evaluated 36

Fig. 1. Historical overview of EGFR-TKIs in perioperative therap.

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C. Grant and M. Nagasaka Cancer Treatment Reviews 126 (2024) 102724

patients with stage I NSCLC who received neoadjuvant gefitinib 250 mg postoperative adjuvant therapy duration, which was left to the in­
treatment for 28 days [27]. In the study, 6 patients harbored an EGFR vestigators selection.
mutation. While 11 % of patients had an overall response rate, 50 % of Subsequently, a single-arm phase II trial was performed at the
patients with an EGFR mutation demonstrated an overall response rate. Shanghai Cancer Center evaluating the use of gefitinib in the neo­
While these results were not as promising in the individuals without an adjuvant setting [33]. 33 patients with stage II-IIIA NSCLC with EGFR
EGFR mutation, it showed a larger response in the patients harboring an exon 19 or 21 L858R mutations were enrolled and treated with preop­
EGFR mutation, showing promise for this population’s use of EGFR-TKIs erative gefitinib 250 mg for 42 days followed by surgical resection. The
in the neoadjuvant setting. ORR was 54.5 % (95 % CI 11.9–40.4) with a mDFS of 33.5 months (95 %
In 2015, Zhong et al. evaluated the role of neoadjuvant treatment in a CI 19.7–47.3). Skin toxicities were prevalent in 68.6 % of individuals;
phase II trial consisting of 24 patients with IIIA-N2 NSCLC stratified by however, none were grade 3 or greater adverse events. While the sample
EGFR-mutant status [28]. Twelve cases with mutant-type EGFR were size was small, this study demonstrated potential benefit from preop­
assigned to receive erlotinib for 42 days with subsequent resection and erative EGFR-TKI treatment.
individuals with wild type-EGFR were assigned to receive gemcitabine/ The ASCENT trial evaluated afatinib in the neoadjuvant setting [34].
carboplatin for 3 cycles then undergo resection. The overall response Patients received afatinib 40 mg daily for two months with concurrent
rate (ORR) was 58.3 % (7/12) and 25 % (3/12) in the erlotinib and the chemoradiation of up to four cycles of cisplatin/pemetrexed and 3D
gemcitabine/carboplatin arms respectively. PFS was 6.9 months (95 % conformal radiotherapy or intensity-modulated radiotherapy. Then pa­
CI 3.8–10.0) and 9.0 months (95 % CI 3.1–15.0) for the erlotinib and the tients went to surgery with two additional years of adjuvant afatinib that
gemcitabine/carboplatin arms respectively. Medians OS was 14.5 was optional. 19 patients were enrolled and had an ORR to neoadjuvant
months (95 % CI 1.0–28.1) and 28.1 months (95 % CI 0.0–66.2) for the afatinib of 58 % (11/19). There were 10 patients deemed resectable with
erlotinib and the gemcitabine/carboplatin arms respectively. Both pre­ all having a lobectomy with a major pathologic response of 70 % (7/10)
operative treatments were well tolerated with minimal toxicities. While after a combination of afatinib and chemoradiation. Unfortunately, the
these findings were impressive, it was important to note that the two study closed due to slow accrual. 9 patients had recurrence with 5 being
populations of mutant-type EGFR and wild type-EGFR are biologically CNS-only recurrence.
distinct populations. Shortly after, afatinib was evaluated in 42 patients in the neo­
Subsequently, Chen et al performed a study using neoadjuvant EGFR- adjuvant setting [35]. The ORR was 70.2 % (95 % CI 56.5–84.0 %). The
TKI treatment for patients with stage IIIA NSCLC to evaluate the feasi­ major pathologic resistance rate was 9.1 % (1.0–24.3 %) with one pa­
bility, efficacy, and safety of TKIs in this population [29]. 86 patients tient receiving pathologic complete response. The most common
were assigned to a neoadjuvant experimental arm using erlotinib 150 treatment-related adverse events were diarrhea (78.7 %) and rash (78.7
mg daily for 9 weeks or two cycles of pemetrexed and cisplatin %).
chemotherapy with subsequent surgical resection. In the experimental Despite demonstration of clinical trials with first- and second-
arm, four patients achieved pCR with an ORR of 67.4 %.. The experi­ generation EGFR-TKIs, the first use of a third-generation EGFR-TKI
mental arm had a 90.7 % resection rate while the control group had an was in a case report of a 64-year-old male with a stage III EGFR exon 19
83.7 % which was not statistically significant. This study suggested that deletion who received osimertinib with neoadjuvant therapy and to date
resection rates are not altered by the additional treatment duration of of the case report the patient was disease-free for four months after
preoperative erlotinib compared to chemotherapy. surgery [36]. The first clinical trial using third-generation EGFR-TKIs
Xiong and colleagues then conducted a single-arm phase II study was the NEOS study, which was a single-arm, phase IIb trial enrolling
evaluating patients with stage IIIA-N2 EGFR mutation-positive NSCLC patients with EGFR-mutant stage IIA-IIIB (T3-4N2) lung adenocarci­
[30]. 19 patients underwent preoperative treatment with erlotinib 150 noma [37]. Thirty-eight patients were treated with osimertinib 80 mg
mg daily for 56 days with 14 patients undergoing surgical resection. The for 6 weeks with subsequent surgical resection. The ORR was 71 % (95
radical resection rate was 68.4 % (13/19) with a 21.1 % (4/19) rate of % CI 55.2–83.0). Thirty-two patients had surgery performed with 93.8
pathologic downstaging. The ORR was 42.1 % and a 51.6-month median % having a successful R0 resection and 41.2 % with lymph node
OS. Adverse effects occurred in 36.8 % of patients with the most com­ downstaging. The toxicities were minimal with 7.5 % (3/40) having
mon being a rash (26.3 %). 15.8 % of patients experienced grade 3 or treatment-related adverse events of grade three consisting of a rash,
greater adverse events. hypertension, and nephrotic syndrome. The most common TRAEs were
The first multicenter trial was coined EMERGING-CTONG 1103, a rash (50 %), diarrhea (30 %), and oral ulcerations (30 %). This sug­
which was an open-label phase II randomized trial comparing erlotinib guested potential benefit for third-generation EGFR-in neoadjuvant
to gemcitabine and cisplatin in the neoadjuvant setting for patients with setting.
stage IIIA-N2 NSCLC with EGFR mutations in exon 19 or 21 [31]. 72 Most recently, a single-arm, phase II clinical trial was presented on
patients were randomly assigned to an experimental arm consisting of 27 patients with stage I-IIIA EGFR exon 19 or L858R mutation NSCLC
erlotinib 150 mg daily for 42 days with postoperative therapy that [38]. Patients were given osimertinib 80 mg daily for up to two 28-day
consisted of up to 12 months or gemcitabine and cisplatin treatment for cycles prior to surgical resection. Patients were treated with osimertinib
two cycles with postoperative therapy for up to two cycles. The ORR for for a median 56 days prior to surgical resection. The primary endpoint
neoadjuvant erlotinib was 54.1 % compared to 34.3 % in the chemo­ was major pathologic response rate which was 15 % (4/15) and a
therapy arm with an odds ratio of 2.26 (95 % CI 0.87–5.84, P = 0.092). pathologic response rate of 45 %. 24 patients underwent subsequent
Median progression free survival was 21.5 months in the erlotinib arm resection without surgical complications. Lymph node downstaging was
compared to 11.4 months in the chemotherapy arm with a hazard ratio achieved in 44 % of patients with positive lymph nodes. mDFS was 32
of 0.39 (95 % CI 0.23–0.67, P < 0.001). Recently the overall survival months (95 % CI 26-not reached). Overall survival had not been ach­
results were published demonstrating a 3-year and 5-year OS rate of ieved at the time of presentation. Significant adverse events occurred in
58.6 % and 40.8 % with erlotinib and 55.9 % and 27.6^% with chemo­ 3 patients with dyspnea (grade 2), pulmonary embolism (grade 3), and
therapy (p3-y = 0.819 and p5-y = 0.252) [32]. This study demonstrated atrial fibrillation (grade 3). Uniquely, tumors were evaluated for genetic
that similar studies are feasible. Additionally, the PFS was statistically alterations from 16 patients. While this study did not meet its achieved
significant; however, the OS rates were not. It is important to note that goal of 15 % MPR, it did show that neoadjuvant targeted therapy is
the 5-year OS was significantly distinct compared to the 3-year OS. It is feasible as the unresectability rate was only 11 % and surgically safe as
hypothesized that this could be due to subsequent lines of treatment that there were no surgical complications. While the MPR wasn’t achieved, it
were utilized. Additionally, these insignificant results could have been could potentially still be effective in a larger sample with a defined
due to the use of a first-generation EGFR-TKI as well as a difference in preoperative duration of treatment. Additionally, RBM10 loss of

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C. Grant and M. Nagasaka Cancer Treatment Reviews 126 (2024) 102724

function (LOF) mutations were evaluated and found to be present in four Table 1
of the six non-responders. Furthermore, increased expression of YAP Clinical trials with reported results for neoadjuvant EGFR-TKI in NSCLC.
target genes were identified at residual disease, suggesting that YAP Study Phase N Stage Therapy Results
activation may drive tumor cell survival, indicating a mechanism of
Schaake 2012 [26] II 15 IIIA Erlotinib x 3 Metabolic
potential resistance. Of these patients, four out of four of those with N2 wks → sx partial
RBM10 LOF were seen in L858F mutations indicating that RBM10 is response 66.6
more common in L858R than in exon 19 deletion. This may indicate that % (10/15)
neoadjuvant treatment could demonstrate a tailored benefit in partic­ Lara-Guerra 2012 [27] II 36 I Gefitinib x In general
28 days → sx population
ular EGFR mutations. without EGFR
Table 1 lists the clinical trials of neoadjuvant EGFR TKIs that have mutation ORR
been reported. 11 %, Of those
with EGFR
mutation,
Ongoing clinical trials – EGFR-TKI monotherapy
ORR 50 %
Zhong 2015 II 24 IIIA Erlotinib x Erlotinib ORR
Currently, several ongoing clinical trials currently exist evaluating NCT00600587 [28] N2 6wks vs GC 58.3 % (7/12)
preoperative EGFR-TKI monotherapy. The National Cancer Center in chemo 3 vs GC chemo
cycles → sx ORR 25 % (3/
Korea is currently performing a single-arm phase II clinical trial
12). mPFS 6.9
(NCT01470716) evaluating preoperative erlotinib for up to 6 weeks in vs 9 and mOS
26 patients with operable stage II or IIIA NSCLC with EGFR mutations in 14.5 and 28.1
exon 19 or 21 [39]. months for
Additionally, Shanghai Zhongshan Hospital is performing a single- erlotinib vs
GC chemo,
arm, phase II clinical trial (NCT0598726) evaluating preoperative fur­
respectively.
monertinib for up to 8 weeks for 40 patients with stage II-IIIB operable Chen 2018 [29] II 86 IIIA Erlotinib x Erlotinib ORR
NSCLC with EGFR mutations [40]. 9wks vs 67.4 % (25/
At Yonsei University, there is a single-arm phase II study evaluating pemetrexed 43) 4 CPR
and cisplatin
surgically resectable stage I-IIIA NSCLC with EGFR 19 del or L858R
2 cycles → sx
where patients will be given preoperative osimertinib 80 mg daily for 8 ESTERN II 19 IIIA Erlotinib x 8 Radical
weeks then undergo surgical treatment (NCT04816838) [41]. Uniquely Xiong 2019 N2 wks → sx resection rate
this study will be evaluating single cell RNA sequencing to characterize NCT01217619 [30] 68.4 % (13/
heterogeneous gene expression and interrelate the transcriptional, 19), path
down staging
functional, and genetic diversity between pre and post immunotherapy
21.1 %, ORR
as well as next generation sequencing to detect mutations. 42.1 %, mPFS
At the Chinese Academy of Medical Science Cancer Hospital, there is 11.2 months,
a single-arm phase II clinical trial evaluating patients with EGFR-mutant mOS 51.6
Stage IIIAN2 NSCLC treating with icotinib 125 mg three times daily for months.
EMERGING-CTONG II 72 IIIA Erlotinib x 6 Erlotinib ORR
eight weeks as neoadjuvant therapy (NCT03749213) [42]. Individuals 1103 N2 wks vs GC 54.1 % (20/
will then receive surgical resection and remain on icotinib until pro­ Zhong 2019 chemo 2 37) vs. GC
gressive disease or unaccepted toxicity for up to two years. NCT01407822 [31] cycles → sx chemo ORR
Additionally, the study ANSWER is a multicenter randomized 34.3 % (12/
35). mPFS
controlled phase II study assessing neoadjuvant treatment of 168 pa­
21.5 vs 11.4
tients with stage IIIA-N2 EGFR-mutated NSCLC (NCT04455594) [43]. and 3 yr-OS
Individuals will be randomized to a trial arm with almonertinib 110 mg 58.6 % vs.
daily or an investigator choice therapy of erlotinib 150 mg, cisplatin/ 55.9 %. 5 yr-
pemetrexed, or carboplatin/pemetrexed for a three-week cycle. This OS 40.8 % vs
27.6 %.
study is also evaluating concordance of EGFRm status between plasma- Zhang 2021 II 33 II- Gefitinib x ORR 54.5 %
derived ctDNA to evaluate the potential utilization as a baseline to NCT01833572 [33] IIIA 6wks → sx (18/35).
define need for adjuvant treatment as well as duration of adjuvant mDFS 33.5
treatment. months
ASCENT II 19 III Afatinib x 8 ORR 58 %
The Shanghai Pulmonary Hospital is evaluating neoadjuvant treat­
Piper-Vallillo 2021 weeks → (11/19). MPR
ment with afatinib in Stage III EGFR-mutant-positive lung adenocarci­ NCT01553942 [34] cisplatin/ in those who
noma through a single-arm phase II clinical trial (NCT04201756) [44]. pemetrexed underwent
The trial was completed; however, results have not been published. and RT → sx resection 70
Forty-seven individuals were given afatinib 40 mg daily for 8–16 weeks → afatinib x % (7/10)
2 yrs
total. Those who responded to afatinib treatment and those were (optional)
deemed surgically resectable received a radical lung lobectomy with Bian 2023 II 47 III Afatinib x ORR 70.2
systematic lymph node dissection. Individuals with a preoperative NCT04201756 [35] 8–16 wks → (33/47). MPR
response to afatinib received postoperative therapy for at least a year. sx 9.1 % (4/47)
NEOS IIb 38 IIA- Osimertinib ORR 71.1 %
NCT06018688 is also a single-arm phase II clinical trial evaluating
Lv 2023 IIIB x 6wks → sx (27/38). R0
neoadjuvant therapy with osimertinib combined with aspirin in EGFR- ChiCTR1800016948 resection
mutated stage IIA-IIIA resectable NSCLC [45]. Given aspirins ability to [37] 93.8 % (30/
inhibit enzymatic activity of acetylheparinase, thereby suppressing 32).Resected
tumor angiogenesis and metastasis, it has been evaluated in a variety of patients with
N2 ->N1 LN
cancers as a potentially angiogenic. This trial will evaluate 44 in­ downstaging
dividuals who will receive preoperative osimertinib 80 mg and aspirin 41.2 % (7/17)
100 mg daily for two months and then subsequently undergo surgical (continued on next page)
resection.

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C. Grant and M. Nagasaka Cancer Treatment Reviews 126 (2024) 102724

Table 1 (continued ) pemetrexed for a total of three 21-day cycles with subsequent surgical
Study Phase N Stage Therapy Results resection.
NeoADAURA is the first phase III randomized multi-center clinical
Aredo 2023 II 27 I-IIIA Osimertinib MPR 5 % (4/
NCT03433469 [38] x 8wks → sx 15). LN
trial evaluating EGFR-TKI treatment in the neoadjuvant setting
downstaging (NCT04351555) [50]. 328 individuals with stage II-IIIB N2 disease will
44 %. mDFS be randomized to either osimertinib 80 mg daily monotherapy, combi­
32 months. nation platinum-based standard of care chemotherapy with osimertinib
mOS not
80 mg daily, or placebo with platinum-based standard of care chemo­
reached
therapy for three 21-day cycles and subsequent operative resection.
After resection, individuals will have the option to stay on osimertinib
See Table 2 for the list of ongoing studies utilizing EGFR-TKIs as for up to three years with or without chemotherapy depending on in­
monotherapy in the neoadjuvant setting. vestigators choice. The primary outcome is MPR with secondary out­
comes including pCR, EFS, OS, DFS, lymph node downstaging. The study
Ongoing clinical trials – Combination EGFR-TKI and will also evaluate the concordance of EGFR mutation status from base­
chemotherapy line tumor samples and plasma concentrations of osimertinib.
Circulating-free tumor DNA is also being evaluating as a biomarker
Furthermore, several clinical trials are also ongoing evaluating the evaluation for MPR. The study is estimated to be completed in June
combination of chemotherapy and treatment with EGFR-TKIs. At Sun 2024.
Yat-Sen University, combination neoadjuvant therapy is being evaluated At the Liaoning Tumor Hospital and Institute, a single-arm phase II
using afatinib and chemotherapy in 30 NSCLC patients for three cycles clinical trial is currently being performed evaluating combination ico­
in the neoadjuvant setting (NCT04470076) [46]. Subsequently after tinib and chemotherapy in 45 patients with resectable stage II-IIIBN2
each cycle of chemotherapy, individuals will then take afatinib 30 mg disease (NCT05132985) [51]. Individuals will be given neoadjuvant
daily starting 48 h after chemotherapy and ending 24 h before the next platinum-based chemotherapy with pemetrexed and icotinib 125 mg
cycle. Surgical resection will be performed and individuals will remain three times a day with surgical resection after cycle 2. Patients will
on adjuvant treatment with afatinib for up to two years. receive an additional two cycles of platinum-based doublet chemo­
Additionally, Sun Yat-Sen university is also evaluating combination therapy with intercalated icotinib that will be continued for up to two
osimertinib and chemotherapy for 30 individuals with stage III NSCLC in years until disease progression or unacceptable toxicities.
a phase II, single-arm clinical trial coined NOCE01 (NCT05011487) Table 3 shows the list of ongoing clinical trials of combination EGFR-
[47]. Individuals will receive osimertinib 80 mg daily for 60 days with TKIs and chemotherapy in the neoadjuvant setting.
two cycles of cisplatin with pemetrexed on day 1 for two 21-day cycles.
NeoIpower is a phase II single-arm clinical trial evaluating neo­ Future directions
adjuvant icotinib and chemotherapy treatment in 27 individuals with
EGFR-mutant resectable stage IIA-IIIB NSCLC (NCT05104788) [48]. Primary and secondary endpoints used in neoadjuvant targeted therapy
Individuals will be given icotinib 125 mg three times a day plus a trials
platinum-based chemotherapy regimen with pemetrexed for two 21-day
cycles without adjuvant therapy. Uniquely, EGFR mutation detection of A variety of primary and secondary endpoints are utilized in clinical
plasma samples will be evaluated to determine if there are alterations in trials. Overall survival has been coined the optimal end point in onco­
the copy number after cycle two cycles of chemotherapy and pre-surgery logic clinical trials, but this data can take 10–15 years to obtain,
compared to prior to initiation of treatment. delaying drug development and creation of standardized guidelines to
FORSEE is a phase II single-arm clinical trial evaluating the use of treat patients [52]. Additionally, effective subsequent therapies can in­
combination chemotherapy with furmonertinib in EGFR-mutated stage fluence OS comparisons [53]. For instance, if a subsequent improved
IIIA-IIIB resectable NSCLC (NCT05430802) [49]. 40 individuals will therapy is given after tumor progression in the control arm when
receive furmonertinib 80 mg daily for nine weeks and cisplatin with compared to the experimental arm, it will lead to a smaller OS difference
than if the therapy was not available. Given this, several surrogate in­
termediate endpoints are being used to evaluate efficacy of neoadjuvant
Table 2 targeted therapy, including major pathologic response, pathologic
Ongoing clinical trials with neoadjuvant EGFR-TKI monotherapy. complete response, and disease-free survival. A meta-analysis evaluating
Study Phase Stage N Therapy Primary surrogate analysis in operable and locally advanced lung cancer found a
endpoint high level of evidence that disease free survival is a valid surrogate
NCT01470716 II II- 26 Erlotinib x 6 wks → PFS endpoint for overall survival in studies of adjuvant chemotherapy for
[39] IIIA sx patients with NSCLC. While this can’t be extrapolated for targeted and
NCT0598726 [40] II II- 40 Furmonertinib x ORR immunotherapy trials, it does suggest that surrogate endpoints can
IIIA 8wks → sx
N2
provide benefit in demonstrating drug efficacy far before OS. Clinical
NCT04816838 II I-IIIA 25 Osimertinib x 8 wks ORR trials evaluating adjuvant EGFR targeted therapy have demonstrated
[41] → sx → Osimertinib mixed results among correlation with OS when compared to interme­
x 3 yrs diate endpoint markers. For instance, the phase III IMPACT study
NCT03749213 II IIIA 36 Icotinib x 8wks → sx ORR
revealed a 2-year DFS rate with adjuvant gefitinib compared to
[42] N2 → Icotinib x 2 yrs
ANSWER II IIIA 168 almonertinib vs ORR chemotherapy; however, this was not seen to translate in OS benefit
(NCT04455594) N2 investigator choice [54]. On the other hand, in ADAURA, updated data showed that DFS did
[43] (erlotinib or chemo) correlate with a meaningful improvement in OS upon follow-up and
-→ sx suggests validation of DFS as a valid intermediate marker for overall
LungMate-004 II III 47 Afatinib x 8-16wks ORR
NCT04201756 → sx → afatinib x 1
survival in the adjuvant setting [55]. Further clinical equipoise exists on
[44] yr which specific intermediate endpoints can act as a meaningful surrogate
NEWCOAST II IIA- 44 Osimertinib and MPR for overall survival and efficacy of treatment.
NCT06018688 IIIA aspirin x 8 wks → sx
[45]

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C. Grant and M. Nagasaka Cancer Treatment Reviews 126 (2024) 102724

Table 3
Ongoing clinical trials with combination neoadjuvant EGFR-TKI and chemotherapy.
Study Phase Stage N Therapy Primary endpoint
(s)

NCT04470076 [46] II IIa-IIIb 30 Platin-based/pemetrexed x 3 21-day cycles with concurrent afatinib during cycles → sx → MRP, ORR
afatinib x 2 yrs
NOCE01
NCT05011487
[47] II III 30 Cisplatin/pemetrexed x 2 21-day cycles with concurrent osimertinib x 60 days → sx Complete LN
clearance
Neolpower NCT05104788 II II-IIIB 27 Platin-based/pemetrexed x 2 21-day cycles with concurrent icotinib x 6 wks → sx MPR
[48]
FORSEE NCT05430802 II IIIA-IIIB 40 Cisplatin/pemetrexed x 3 21-day cycles with concurrent furmonertinib x 9 wks → sx ORR
[49]
NeoADAURA III II-IIIB 328 neoadjuvant chemo + placebo vs chemo + osimertinib vs osimertinib 9 wks → sx → investigator MPR
(NCT04351555) [50] (N2) choice (osimertinib x 3yrs +/- chemo)
NCT05132985 [51] II II-IIIB 45 Platin-based/pemetrexed x 2 21-day cycles with concurrent icotinib → sx → platin-based doublet MPR
N2 chemotherapy x 2 21-day cycles with icotinib x 2 yrs

Identifying various targeted therapy mechanisms that benefit C767S-mutant EGFR [64]. Dual-targeted and combination of targeted
therapy inhibitors have also been effective in vitro and in vivo against
In addition to EGFR mutations, there are several other molecular acquired mutations and yield promising potential [65,66]. Additionally,
alterations that warrant evaluation in the neoadjuvant setting. ALNEO is the combination of targeted therapy with chemotherapy such as
a phase II trial assessing the activity of neoadjuvant alectinib in 33 pa­ cisplatin or pemetrexed is also being investigated in pre-clinical models
tients with potentially resectable stage III ALK-positive NSCLC [56]. as a potential to prevent acquired resistance [67].
Individuals will be treated with neoadjuvant alectinib 600 mg twice In treatment with neoadjuvant targeted therapy, patients undergo
daily for eight weeks before undergoing surgical intervention with treatment with a drug for a specified amount of time and then undergo
adjuvant treatment for up to 96 weeks until progression of disease or surgical intervention. In the time between their last dosage of targeted
treatment toxicity. therapy and resumption of targeted therapy in the adjuvant setting, it is
NAUTIKA1 is a study evaluating neoadjuvant treatment with various unclear if there is a higher propensity of the development of acquired
types of molecular alterations including ALK, ROS1, NTRK, RET, and resistance mechanisms. Further research is necessary to understand if
BRAFV600E in 80 patients for eight weeks of neoadjuvant treatment and how resistance will occur during this time period.
with surgical resection and subsequent chemotherapy with targeted
therapy treatment for a total of up to two years [57]. Geometry-N is a Duration of adjuvant treatment with targeted therapy and use of
clinical trial evaluating neoadjuvant treatment with capmatinib usage biomarkers
on individuals with a MET exon 14 skipping mutation [58]. Libretto-001
is a clinical trial evaluating neoadjuvant treatment with selpercatinib in While preoperative therapy provides treatment before definitive
individuals with RET inhibitor mutations [59]. surgical treatment, the role of adjuvant therapy is to eliminate residual
Given the numerous specific molecular mechanisms that targeted cancer after surgery to decrease the recurrence rate of disease. Many
therapies have the potential to treat, patients may have a lung cancer studies are utilizing adjuvant treatment for 2 years or until disease
that demonstrates multiple mutations. Recently, drug synergy has been progression or toxicity. Randomized clinical trials are needed to eval­
evaluated to determine the potential role when treating lung cancer uate the role of adjuvant therapy in targeted treatments.
[60]. Nair et al. evaluated more than 5,000 drug combinations across 81 Several questions are needed to be addressed. First, what is the ideal
cancer cell lines of NSCLC to identify drug combinations that would be duration of targeted therapy in the adjuvant setting? Does complete
synergistic [61]. The results showed that drug combinations rarely pathologic response alter the needed duration of adjuvant treatment?
result in strong gain in efficacy. There was a gain of activity when CtDNA clearance during treatment has been shown in a real-world study
cotargeting functionally proximal genes, offering a potential drug to suggest that it may serve as a predictive and prognostic marker [68].
development strategy to yield higher results of synergistic effects. This Checkmate-816 and IMpower-010 demonstrated that ctDNA clearance
sugguests there may be a benefit of combination therapy in some situ­ in the posttreatment setting was associated with improved pathologic
ations, such as when genes are functionally proximal. complete response and disease-free survival [8,69,70]. It is unclear if
neoadjuvant targeted therapy trials will yield similar findings. Addi­
Alteration in resistance mutations tionally, there is emerging evidence that other novel biomarkers such as
circulating tumor RNA, exomes, and proteins could provide additional
EGFR-TKI treatment usage has been impacted by the development of insight into disease progression and prediction of treatment response
either intrinsic or acquired resistance. Several theories have been [71].
described such as the occurrence of secondary mutations, activation of
alternative signaling, divergence of the downstream pathways, and Where do we find patients: lung cancer screening
impairment of the EGFR-TKI mediated apoptosis pathway [62]. Specif­
ically in treatment with osimertinib in EGFR-activating mutations, an Currently, annual lung cancer screening is dedicated to adults aged
analysis was done highlighting molecular mechanisms specifically after 50–80 years old who have a 20-pack year smoking history and currently
treatment with osimertinib. Studies have found that MET/HER2 ampli­ smoke or have quit within the past 15 years [72]. Recently, a meta-
fication, activation of the RAS-mitogen-activated protein kinase, or RAS- analysis of 14 lung cancer screening studies concluded that the relative
phosphatidylinositol 3-kinase pathways, novel fusion events, and his­ risk of lung cancer detected by low dose CT screening was 1.22 (95 % CI:
tological/phenotypical transformation are the many ways osimertinib 0.89–1.68) for Asian female never-smokers and male ever-smokers
acquired and intrinsic resistance are present [63]. which is statistically similar [73]. The authors also found that more
To overcome these intrinsic mutations, fourth generation EGFR-TKIs lung cancers were diagnosed at first scan in Asian female never-smokers
are being developed to overcome common tertiary mutations, such as (95.4 % [95 % CI: 79.3–95.4]) compared to ever-smokers (70.9 % [95 %

6
C. Grant and M. Nagasaka Cancer Treatment Reviews 126 (2024) 102724

CI: 71.1–87.4) (p = 0.010). Additionally, more stage I lung cancers were [13] Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in
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found in never-smokers (88.5 % [95 % CI: 79.3–95.4]) when compared
growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial.
to ever-smokers (79.7 % [95 % CI 71.1–87.4], p = 0.071). Another Lancet Oncol 2010;11:121–8.
recent study also highlighted that the majority of patients with resect­ [14] Oxnard GR, Arcila ME, Sima CS, et al. Acquired resistance to EGFR tyrosine kinase
able lung cancers had lung cancer identified incidentally and not inhibitors in EGFR mutant lung cancer: distinct natural history of patients with
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lecular mechanisms targetable through therapy [75,76]. [19] Wu Y-L, Tsuboi M, He J, et al. Osimertinib in resected EGFR -mutated non–small-
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[20] Herbst RS, Tsuboi M, John T, et al. Overall survival analysis from the ADAURA trial
Conclusion of adjuvant osimertinib in patients with resected EGFR-mutated (EGFRm) stage
IB–IIIA non-small cell lung cancer (NSCLC). https://doi.org/101200/JCO20234117_
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CRediT authorship contribution statement review of the literature. https://doi.org/101177/030089161309900522 2018; 99:
e241–e244.
Christopher Grant: Data curation, Formal analysis, Investigation, [26] Schaake EE, Kappers I, Codrington HE, et al. Tumor response and toxicity of
neoadjuvant erlotinib in patients with early-stage non-small-cell lung cancer. J Clin
Validation. Misako Nagasaka: Conceptualization, Supervision, Re­
Oncol 2012;30:2731–8.
sources, Formal analysis, Validation, Writing – review & editing. [27] Lara-Guerra H, Chung CT, Schwock J, et al. Histopathological and
immunohistochemical features associated with clinical response to neoadjuvant
gefitinib therapy in early stage non-small cell lung cancer. Lung Cancer 2012;76:
Declaration of competing interest 235–41.
[28] Zhong W, Yang X, Yan H, et al. Phase II study of biomarker-guided neoadjuvant
treatment strategy for IIIA-N2 non-small cell lung cancer based on epidermal
The authors declare the following financial interests/personal re­ growth factor receptor mutation status. J Hematol Oncol 2015;8:1–10.
lationships which may be considered as potential competing interests: [29] Chen WQ, Li P, Wang Q, et al. A randomized controlled study of erlotinib versus
Dr. Grant has no potential conflicts to disclose. Dr. Nagasaka has pemetrexed combined with cisplatin in neoadjuvant therapy of stage IIIA EGFR-
mutant lung adenocarcinoma. Zhonghua Zhong Liu Za Zhi 2018;40:133–7.
received consulting fees from Cari Life Sciences, honoraria from Astra­ [30] Xiong L, Li R, Sun J, et al. Erlotinib as neoadjuvant therapy in stage IIIA (N2) EGFR
Zeneca, Daiichi Sankyo, Novartis, Lilly, Pfizer, EMD Serono, Regeneron, mutation-positive non-small cell lung cancer: a prospective, single-arm, phase II
BMS, Genentech, Mirati, Takeda, Janssen, Blueprint Medicine and travel study. Oncologist 2019;24. 157-e64.
[31] Zhong WZ, Chen KN, Chen C, et al. Erlotinib versus gemcitabine plus cisplatin as
support from AnHeart Therapeutics.
neoadjuvant treatment of stage IIIA-N2 EGFR-mutant non-small-cell lung cancer
(EMERGING-CTONG 1103): a randomized phase II study. J Clin Oncol 2019;37:
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