CT has remained the only therapeutic standard-of-care option in the adjuvant setting for almost two decades. Only in most recent years, with the revolution of immunotherapy and new targeted therapies for oncogene-addicted disease in the advanced setting, the opportunity to exploit the possible benefit deriving from these new treatment options in earlier stages has been taken into consideration. In this way, while molecular testing and Programmed death-ligand 1 (PD-L1) evaluation have become mandatory over the years in advanced NSCLC to identify predictive factors for new therapies, it has not been historically required as a routine in stage I-III disease: it represents only a recent addiction in early-stage NSCLC patients (pts) due to the several clinical trials conducted both in the adjuvant and neoadjuvant setting.
Far less common are ROS Proto-Oncogene 1 (ROS1), RET or Neurotrophic Tyrosine Receptor Kinase (NTRK) 1–3 genes rearrangements, or BRAF, HER2 or MET gene alterations. All these drivers, as well as the more common KRAS gene mutations, have not been a specific focus of research yet for phase III clinical trials in early-stage NSCLC.
As regards immunotherapy trials, pharmacological agents have been variably tested both considering and irrespective of PD-L1 evaluation on tumor cells.
In the numerous completed or still ongoing trials with TKIs and ICIs, drugs have been experimented with after standard platinum-based adjuvant CT or as a replacement to it. This still remains an open question, whether postoperative CT can be actually superseded in biomarker-selected pts candidates to adjuvant new generation therapies.
2. EGFR Tyrosine Kinase Inhibitors
2.1. Adjuvant Setting
It is reported that pts with common EGFR mutations (exon 19 deletion (Ex19del) and exon 21 L858R mutation) typically have a shorter DFS after radical surgery, even if receiving standard platinum-based adjuvant CT
[7]. Also considering the poorer prognosis of these pts, several clinical trials have explored the DFS benefit of EGFR-TKIs in the adjuvant setting.
The
BR19 trial (NCT00049543) was the first phase III trial to evaluate
gefitinib, a first-generation EGFR-TKI
[8]. 503 pts with stage IB-IIIA resected NSCLC and not selected by EGFRm received either oral gefitinib 250 mg die or placebo for up to 2 years after postoperative radiotherapy and eventual CT. No benefit was reported, neither in DFS (HR 1.22, 95% CI 0.93–1.61,
p = 0.15), nor in overall survival (OS) (HR 1.24, 95% CI 0.94–1.64,
p = 0.14). No benefit was evidenced also in the small subgroup of EGFRm pts (4 out of 359 with known EGFR status). The trial was prematurely closed (an enrollment of 1242 pts had been planned).
The phase III
ADJUVANT-CTONG1104 trial (NCT01405079) enrolled 222 pts with resected stage II-IIIA EGFRm NSCLC
[9]. They were randomized to gefitinib 250 mg die for 2 years or standard adjuvant CT with cisplatin-vinorelbine for 4 cycles. Median DFS was significantly longer in the experimental arm (30.8 vs. 19.8 months (m), HR 0.56, 95% CI 0.40–0.79,
p = 0.001), with a DFS rate at 3 and 5 years of 39.6% vs. 32.5% and 22.6% vs. 23.2%, respectively. The benefit in DFS did not translate to survival, with a not statistically significant OS advantage (median of 75.5 vs. 62.8 m, HR 0.92, 95% CI 0.62–1.36,
p = 0.674). Subsequent treatments received after disease relapse mostly contributed to OS (median not reached with other treatments received vs. 62.8 m with no other lines), especially if subsequent EGFR-TKIs were used (HR 0.23).
The phase III
IMPACT trial (UMIN000006252) randomized 234 pts with stage II-III EGFRm NSCLC to 2 years of gefitinib or standard adjuvant CT
[10]. The experimental arm showed a numerical benefit in DFS which was not statistically significant (median of 35.9 vs. 25.1 m, HR 0.92, 95% CI 0.67–1.28,
p = 0.63); DFS rates at 5 years were 31.8% and 34.1% in the two arms. No difference in OS was reported (HR 1.03, 95% CI 0.65–1.65,
p = 0.89; OS rates at 5 years 78.0% vs. 74.6%).
RADIANT phase III trial (NCT00373425) evaluated the benefit from another first-generation EGFR-TKI,
erlotinib [11]. 973 stage IB-IIIA pts with EGFR-expressing tumors (either ≥ 1% staining at immunohistochemistry (IHC) or gene amplification at fluorescence in situ hybridization (FISH)) were randomized to erlotinib 150 mg die or placebo for 2 years after adjuvant CT. No significant difference in DFS (median of 50.5 vs. 48.2 m, HR 0.90, 95% CI 0.74–1.10,
p = 0.324) and OS (median not reached, HR 1.13, 95% CI 0.88–1.45,
p = 0.335) was reported between treatment arms. 161 pts (16.5%) were EGFRm and a DFS benefit was observed in this subgroup (median of 46.4 vs. 28.5 m, HR 0.61, 95% CI 0.38–0.98,
p = 0.039), even if not statistically significant due to the hierarchical structure of the trial. Also, the phase II trial
SELECT (NCT00567359) experimented erlotinib in stage IA-IIIA NSCLC pts
[12]. 100 pts with EGFRm received erlotinib for 2 years, after adjuvant CT and eventual radiotherapy. Median DFS and OS were not reached, with 5-year DFS and OS rates of 56% (95% CI 45–66) and 86% (95% CI 77–92), respectively. The primary endpoint was a 10% improvement of the 2-year DFS rate in comparison to historical control, which was reached (88% vs. 76%,
p = 0.0047).
EVAN (NCT01683175, phase II) assessed erlotinib in resected EGFRm NSCLC pts with stage IIIA only
[13]. 102 pts were randomized to erlotinib for 2 years or standard adjuvant CT, with a reported benefit in DFS rate at 2 years of 36.7% (95% CI 15.5–58.0,
p = 0.0007), 81.4% vs. 44.6% in the two arms, respectively (RR 1.82, 95% CI 1.19–2.78,
p = 0.0054); median DFS was 42.4 vs. 21.0 m (HR 0.27, 95% CI 0.14–0.53,
p < 0.0001). At a following update
[14], a benefit was described also for OS (median of 84.2 vs. 61.1 m, HR 0.32, 95% CI 0.15–0.67), with a 5-year OS rate of 84.8% vs. 51.1%.
The possible benefit derived from
icotinib, another EGFR-TKI, was evaluated in the
EVIDENCE trial (NCT02448797, phase III), in which 322 stage II-IIIA EGFRm NSCLC pts were randomized to icotinib 125 mg × 3 die for 2 years or standard CT
[15]. A DFS benefit was evidenced, with a median of 47.0 vs. 22.1 m (HR 0.36, 95% CI 0.24–0.55,
p < 0.0001) and a 3-year DFS rate of 63.9% vs. 32.5%. Data on OS are still immature (HR 0.91, 95% CI 0.42–1.94).
Finally,
ADAURA (NCT02511106) is a phase III trial in which 682 stage IB-IIIA EGFRm NSCLC pts were randomized to receive either
osimertinib 80 mg die orally or placebo for up to 3 years, after having received or not adjuvant CT
[16][17]. Considering stage II-IIIA pts only (470, i.e., 69%), in which DFS benefit was evaluated as the primary endpoint, median DFS was not reached but an 83% risk reduction for disease relapse or death was evidenced (HR 0.17, 99% CI 0.11–0.26,
p < 0.001) at an interim analysis. DFS benefit was maintained also in the overall population (HR 0.20, 99% CI 0.14–0.30,
p < 0.001) and was independent of disease stage and from having received adjuvant CT (60% of pts) or not (HR 0.16 with 95% CI 0.10–0.26 and HR 0.23 with 95% CI 0.13–0.40, respectively). OS data were immature, with a 2-year OS rate of 98% vs. 85%. A significant reduction in central nervous system (CNS) recurrence was reported in the experimental arm (HR 0.18, 95% CI 0.10–0.33).
In all the aforementioned trials enrolling EGFRm pts, common mutations (Ex19del and exon 21 L858R mutation) were considered. Data from all the completed/concluding clinical trials with EGFR-TKIs in the adjuvant setting are summarized in Table 1.
Table 1. Clinical trials with available data with EGFR-TKIs in the adjuvant setting.
Clinical Trial |
Phase |
N° pts a |
Years |
Stage |
Treatment Arms |
DFS |
OS |
BR19 [8] (NCT00049543) |
III |
503 (EGFRm- unselected) |
2002–2005 |
IB-IIIA |
Gefitinib × 2 y vs. placebo (after adj CT) (1:1) |
No difference (HR 1.22, 95% CI 0.93–1.61, p = 0.15) |
No difference (HR 1.24, 95% CI 0.94–1.64, p = 0.14) |
ADJUVANT-CTONG1104 [9] (NCT01405079) |
III |
222 |
2011–2014 |
II-IIIA |
Gefitinib × 2 y vs. adj CT (1:1) |
30.8 vs. 19.8 m (HR 0.56, 95% CI 0.40–0.79, p = 0.001) |
75.5 vs. 62.8 m (HR 0.92, 95% CI 0.62–1.36, p = 0.674) |
IMPACT [10] (UMIN000006252) |
III |
234 |
2011–2015 |
II-III |
Gefitinib × 2 y vs. adj CT (1:1) |
35.9 vs. 25.1 m (HR 0.92, 95% CI 0.67–1.28, p = 0.63) |
No difference (HR 1.03, 95% CI 0.65–1.65, p = 0.89) |
RADIANT [11] (NCT00373425) |
III |
973 (‘EGFR- positive’) |
2007–2010 |
IB-IIIA |
Erlotinib × 2 y vs. placebo (after adj CT) (2:1) |
50.5 vs. 48.2 m (HR 0.90, 95% CI 0.74–1.10, p = 0.324) |
Not reached (HR 1.13, 95% CI 0.88–1.45, p = 0.335) |
SELECT [12] (NCT00567359) |
II |
100 |
2008–2012 |
IA-IIIA |
Erlotinib × 2 y (after adj CT) |
Not reached (5-year DFS rate 56%) |
Not reached (5-year OS rate 86%) |
EVAN [13][14] (NCT01683175) |
II |
102 |
2012–2015 |
IIIA |
Erlotinib × 2 y vs. adj CT (1:1) |
42.4 vs. 21.0 m (HR 0.27, 95% CI 0.14–0.53, p < 0.0001) |
84.2 vs. 61.1 m (HR 0.32, 95% CI 0.15–0.67) |
EVIDENCE [15] (NCT02448797) |
III |
322 |
2015–2019 |
II-IIIA |
Icotinib × 2 y vs. adj CT (1:1) |
47.0 vs. 22.1 m (HR 0.36, 95% CI 0.24–0.55, p < 0.0001) |
Not reached (HR 0.91, 95% CI 0.42–1.94) |
ADAURA [16][17] (NCT02511106) |
III |
682 |
2015–2019 |
IB-IIIA |
Osimertinib × 3 y vs. placebo (after adj CT or not) (1:1) |
Not reached vs. 27.5 m (HR 0.20, 99% CI 0.14–0.30, p < 0.001) b |
Not reached (2-year OS rate 98% vs. 85%) b |
Several clinical trials with EGFR-TKIs in the adjuvant setting are currently ongoing (Table 2), evaluating the survival benefits both from first-, second-, or third-generation TKIs (i.e., gefitinib, erlotinib, icotinib, afatinib, osimertinib) and new molecules (i.e., furmonertinib, almonertinib).
Table 2. Ongoing clinical trials with EGFR-TKIs in the adjuvant setting.
Clinical Trial |
Phase |
N° pts |
Estimated Primary Completion |
Stage |
Treatment Arms |
Primary Endpoint |
NCT02518802 |
III |
220 |
Jan 2018 |
II-IIIA |
Gefitinib × 2 y started during or after CT vs. adj CT |
DFS |
NCT03381430 |
II |
50 |
Mar 2023 |
IIIA N2 |
Gefitinib × 2 y + adj RT |
DFS |
NCT02193282 |
III |
450 a |
Oct 2026 |
IB-IIIA |
Erlotinib × 2 y vs. placebo (after adj CT) |
OS |
ICWIP [18] (NCT02125240) |
III |
124 |
Dec 2018 |
II-IIIA |
Icotinib × 3 y vs. placebo |
DFS |
ICTAN (NCT01996098) |
III |
318 |
Jan 2020 |
II-IIIA |
Icotinib × 6 m vs. icotinib × 12 m vs. observation (after adj CT) |
DFS |
NCT03983811 |
III |
174 |
Oct 2021 |
IIB-IIIA |
Icotinib/placebo on days 8–15 during adj q21 CT cycles, then × 2 y |
DFS |
CORIN (NCT02264210) |
II |
128 |
Dec 2025 |
IB |
Icotinib × 12 m vs. observation |
DFS |
NCT01746251 |
II |
92 |
Nov 2020 |
I-III |
Afatinib × 3 m vs. afatinib × 2 y |
RFS |
ADAURA2 (NCT05120349) |
III |
380 |
Aug 2027 |
IA2-IA3 |
Osimertinib × 3 y vs. placebo |
DFS |
FORWARD (NCT04853342) |
III |
318 |
Dec 2023 |
II-IIIA |
Furmonertinib vs. placebo (after adj CT) |
DFS |
ATHEM (NCT05165355) |
II |
90 |
Nov 2024 |
IB-IIA b |
Furmonertinib × 3 y |
DFS |
NCT04687241 |
III |
192 |
Jan 2026 |
II-IIIB N2 |
Almonertinib vs. placebo (after adj CT) |
DFS |
APEX (NCT04762459) |
III |
606 |
May 2026 |
II-IIIA |
Almonertinib × 3 y vs. almonertinib + adj CT vs. adj CT (3:2:1) |
DFS |
Considering the available literature data from trials with concluded enrollment and completed or interim analyses, different EGFR-TKIs have shown a DFS benefit in EGFRm pts in comparison to standard adjuvant CT or as an addition to CT alone: gefitinib for 2 years after CT (ADJUVANT-CTONG1104), erlotinib for 2 years both after (SELECT, even if phase II and with immature data) or instead of CT (EVAN, phase II), icotinib for 2 years instead of CT (EVIDENCE), osimertinib for 3 years possibly after CT (ADAURA). However, no phase III trial has shown an OS benefit yet, with particular reference to all the trials with gefitinib, which already have mature data.
Several discussions have been made on the effective capacity of EGFR-TKIs to actually prevent disease recurrence, rather than simply delaying it. Keeping the focus on gefitinib, the DFS benefit appeared as a minimum, with disease relapse within 1 median year from experimental therapy completion; treatment arms had Kaplan-Meier survival curves crossing around 4 years after surgery and similar 5-year DFS rates (31.8% vs. 34.1% in IMPACT, 22.6% vs. 23.2% in ADJUVANT-CTONG1104). From these considerations, also a question on which is the optimal EGFR-TKI treatment duration arises, examining the brief disease-free interval after therapy interruption. ADAURA has been the only trial in which the adjuvant targeted therapy has been prolonged from 2 to 3 years.
Distinct meta-analyses have analyzed the comprehensive data and survival benefits with the different EGFR-TKis. Yin et al.
[19] considered 11 studies with a total of 1900 EGFRm pts included and reported a DFS benefit with an HR of 0.42 (95% CI 0.31–0.57) and an OS benefit with an HR of 0.62 (95% CI 0.45–0.86). Chen et al.
[20], with 7 randomized clinical trials considered and 1283 EGFRm pts included, reported similar data for DFS benefit (HR 0.41, 95% CI 0.24–0.70,
p = 0.001) but no statistically significant OS benefit (HR 0.72, 95% CI 0.37–1.41,
p = 0.336).
The published data with osimertinib certainly appear encouraging, with an unprecedented benefit in terms of DFS: an HR of 0.17 in the population considered for the primary endpoint and of 0.20 in the overall population. ADAURA also presented an important reduction in CNS recurrence in comparison to other EGFR-TKIs, which is coherent with the known superior CNS activity of osimertinib
[21]. In this way, considering efficacy and safety data, ADAURA brought to a change in clinical practice, with the Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval of osimertinib as the first targeted therapy available in the adjuvant setting for NSCLC pts. Longer follow-up and OS data maturity are anyway expected to confirm the magnitude of its effectiveness.
Since ADAURA allowed osimertinib administration both with and without previous adjuvant CT (and DFS benefit appeared as independent from CT) and considering that other trials showing DFS benefit (ADJUVANT-CTONG1104, EVAN, EVIDENCE) used EGFR-TKIs without CT, there is still no conclusive answer to whether these drugs should be employed with or without other antineoplastic agents.
2.2. Neoadjuvant Setting
The already available published data in the neoadjuvant setting derive from small phase II trials with first-generation EGFR-TKIs. NCT00188617
[22] was the first one to evaluate neoadjuvant
gefitinib for 28 days in 36 stage I NSCLC pts non selected for EGFRm. In NCT00600587
[23], stage IIIA(N2) EGFRm pts were assigned to neoadjuvant
erlotinib while pts without EGFRm received only CT. Objective response rate (ORR) was numerically higher in the experimental arm (58.3% vs. 25.0%). Also NCT01217619
[24] evaluated neoadjuvant erlotinib in the same setting of stage IIIA(N2) EGFRm pts, with a reported ORR of 42.1%.
In the
EMERGING-CTONG1103 (NCT01407822) phase II trial
[25], neoadjuvant erlotinib was compared with carboplatin-gemcitabine CT in stage IIIA EGFRm pts, with the possibility to continue the same therapy in each treatment arm also in the adjuvant setting. The 3-year and 5-year OS rates were 58.6% vs. 55.9% (
p = 0.819) and 40.8% vs. 27.6% (
p = 0.252), respectively.
Other trials are assessing the efficacy of targeted therapy started in the neoadjuvant setting and possibly continued even after surgery (Table 3). In particular, NeoADAURA (NCT04351555) is evaluating the benefit from neoadjuvant osimertinib, both in combination with CT for 3 cycles and alone for at least 9 weeks, in comparison to standard CT. CT and/or osimertinib can then be considered also in the adjuvant setting.
Table 3. Ongoing clinical trials with EGFR-TKIs in the neoadjuvant (+adjuvant) setting.
Clinical Trial |
Phase |
N° pts |
Estimated Primary Completion |
Stage |
Treatment Arms |
Primary Endpoint |
NCT03656393 |
III |
48 |
Jul 2020 |
II-IIIA |
Gefitinib × 56 d vs. CT × 6 w (+ adj CT if not responding disease) |
2-year DFS rate |
NCT03203590 |
III |
590 |
Jan 2026 |
II-IIIA |
Gefitinib × 8 w vs. CT × 2 cycles |
2-year DFS rate |
NCT03749213 |
II |
36 |
Feb 2022 |
IIIA N2 |
Neoadj icotinib × 8 w, then × 2 y after surgery |
ORR |
Neoafa (NCT04470076) |
II |
30 |
Dec 2021 |
II-IIIB |
Neoadj CT + afatinib (48 h after and until 24 h before CT) × 3 cycles, then adj afatinib × 2 y after surgery |
MPR, ORR |
NCT03433469 |
II |
27 |
Dec 2022 |
I-IIIA |
Neoadj osimertinib × 1–2 cycles |
MPR |
NeoADAURA [26] (NCT04351555) |
III |
328 |
Mar 2024 |
II-IIIB N2 |
Neoadj osimertinib + CT × 3 cycles vs. placebo + CT vs. osimertinib alone (1:1:1) |
MPR |
3. ALK Tyrosine Kinase Inhibitors
As described for EGFRm pts, it has been reported that also ALKr are associated with a worse prognosis in resected NSCLC pts
[27][28]. However, literature data are not univocal and even if ALKr tumors are described as clinically aggressive, often with lymph nodes involvement despite low T stage
[29], the effective prognostic significance of ALKr in resected NSCLC remains unsettled
[5][30][31].
In comparison to the EGFRm disease, far less clinical trials have been investigating the role of specific TKIs in the ALKr early disease, with no currently published data available. Several trials are presently ongoing (Table 4).
Table 4. Ongoing clinical trials with ALK-TKIs in the (neo-)adjuvant setting.
Clinical Trial |
Phase |
N° pts |
Estimated Primary Completion |
Stage |
Treatment Arms |
Primary Endpoint |
ALCHEMIST [32] (NCT02194738) |
III |
8300 a |
Sep 2026 |
IB-IIIA |
Crizotinib × 2 y vs. observation (after adj CT) |
OS |
ALINA [33] (NCT03456076) |
III |
257 |
Jun 2023 |
IB-IIIA |
Alectinib × 2 y vs. adj CT |
DFS |
NCT05341583 |
III |
202 |
Jun 2025 |
II-IIIB |
Ensartinib × 2 y vs. placebo |
DFS |
NCT05186506 |
II |
152 |
Dec 2025 |
II-IIIA |
Ensartinib × 2 y vs. adj CT |
DFS |
NCT05241028 |
II |
80 |
Feb 2027 |
IB-IIIA |
Ensartinib × 3 y (after adj CT) |
3-year DFS rate |
ALNEO [34] (NCT05015010) |
II |
33 |
May 2023 |
III |
Neoadj alectinib × 8 w, then adj × 96 w after surgery |
MPR |
NAUTIKA1 (NCT04302025) |
II |
80 a |
Mar 2023 |
IB-III |
Neoadj alectinib × 8 w, then adj CT and alectinib × 2 y |
MPR |
ALCHEMIST (NCT02194738) is a large phase III trial in which 8300 pts with resected stage IB-IIIA NSCLC are tested for gene driver alterations in order to optimize their adjuvant treatment with targeted therapies
[32]. Pts in the ALKr arm are being randomized to
crizotinib 250 mg × 2 die for 2 years or observation after standard adjuvant CT.
Phase III
ALINA trial (NCT03456076) is randomizing stage IB-IIIA ALKr NSCLC pts to either
alectinib 600 mg × 2 die for 2 years or adjuvant CT
[33].