The scenario of neoadjuvant and adjuvant settings in non-small cell lung cancer (NSCLC) is rapidly evolving. As already happened for the advanced disease, also early stages have entered the era of precision medicine, with molecular analysis and Programmed death-ligand 1 (PD-L1) evaluation that by now can be considered a routine assessment. New treatment options have been recently approved, with osimertinib now part of clinical practice for Epidermal Growth Factor Receptor mutated (EGFRm) patients, and immune checkpoint inhibitors (ICIs) available after FDA approval both in the adjuvant (atezolizumab) and neoadjuvant (nivolumab) setting. No mature data on overall survival benefits are available yet, though. Several clinical trials with specific-tyrosine kinase inhibitors (TKIs) and ICIs are currently ongoing, both with and without concomitant chemotherapy. As therapeutic strategies are rapidly expanding, quite a few questions remain unsettled, such as the optimal duration of adjuvant targeted therapy or the effective benefit of ICIs in early-stage EGFRm or ALK (Anaplastic Lymphoma Kinase) rearranged patients, or the possibility to individuate high-risk patients after surgical resection assessing minimal residual disease (MRD) by ctDNA evaluation.
Clinical Trial | Phase | N° pts a | Years | Stage | Treatment Arms | DFS | OS |
---|---|---|---|---|---|---|---|
Clinical Trial | Phase | N° pts | Estimated Primary Completion | Stage | Treatment Arms | Primary Endpoint | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
(NCT00049543) | III | NCT03656393503 (EGFRm- |
III unselected) |
2002–2005 | IB-IIIA | 48 | Jul 2020 | II-IIIA | Gefitinib × 56 d vs. CT × 6 w (+ adj | |||||||||
ALCHEMIST [34 | 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 [11][ | ||||||||||||||||||
IMPACT [12][10] | ||||||||||||||||||
NCT02518802 | III | ]220 | Jan 2018 | [II-IIIA | 32Gefitinib × 2 y started during or after CT vs. adj CT |
DFS | ] (NCT02194738) |
III | 8300 a | Sep 2026CT if not responding disease) | 2-year DFS rate | |||||||
9] (NCT01405079) | III | 222 | 2011–2014 | II-IIIA | Gefitinib × 2 y vs. adj CT (1:1) |
30.8 vs. 19.8 m | ||||||||||||
NCT03381430 | (HR 0.56, 95% CI 0.40–0.79, | II | p | = 0.001) | ||||||||||||||
IB-IIIA | Crizotinib × 2 y vs. observation | (after adj CT) | OS | NCT0320359050 | III | 75.5 vs. 62.8 m | 590 (HR 0.92, 95% CI 0.62–1.36, |
Mar 2023 | Jan 2026 | II-IIIA | ||||||||
ALINA [ | Gefitinib × 8 w vs. CT × 2 cycles | 35][ | 2-year DFS rate | p | = 0.674) | |||||||||||||
IIIA N2 | Erlotinib × 2 y vs. placebo | (after adj CT) | ||||||||||||||||
33] (NCT03456076) |
III | 257 | Gefitinib × 2 y + adj RT | DFS | Jun 2023 | IB-IIIA | Alectinib × 2 y vs. adj CT | DFS | (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 | OS (HR 1.03, 95% CI 0.65–1.65, p | |
NCT02193282 | = 0.89) | |||||||||||||||||
III | 450 | a | ||||||||||||||||
NCT03749213 | II | Oct 2026 | 36 | IB-IIIA | Feb 2022 | IIIA N2 | Neoadj icotinib × 8 w, then × 2 y after surgery |
ORR | RADIANT [ | |||||||||
NCT05341583 | III | 202 | Jun 2025 | II-IIIB | Ensartinib × 2 y vs. placebo | DFS | 13][11] (NCT00373425) |
ICWIPIII | 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) |
||||
[20][18] (NCT02125240) |
III | 124 | Dec 2018 | II-IIIA | Icotinib × 3 y vs. placebo | NeoafaDFS | ||||||||||||
(NCT04470076) |
II | 30 | Dec 2021 | II-IIIB | SELECT [14 | |||||||||||||
NCT05186506 | II | Neoadj CT + afatinib (48 h after and | 152 | until 24 h before CT) × 3 cycles, then adj afatinib × 2 y after surgery |
MPR, ORR | ][ | ICTAN12] (NCT01996098) |
III | 318 | Jan 2020 | ||||||||
Dec 2025 | II-IIIA | Ensartinib × 2 y vs. adj CT | DFS | (NCT00567359) | II | 100 | 2008–2012 | IA-IIIA | II-IIIAErlotinib × 2 y (after adj CT) |
Icotinib × 6 m vs. icotinib × 12 m vs. observation (after adj CT)Not reached (5-year DFS rate 56%) |
Not reached (5-year OS rate 86%) |
|||||||
DFS | ||||||||||||||||||
NCT03433469 | II | 27 | Dec 2022 | I-IIIA | Neoadj osimertinib × 1–2 cycles | MPR | ||||||||||||
NCT05241028 | II | 80 | Feb 2027 | IB-IIIA | Ensartinib × 3 y (after adj CT) | 3-year DFS rate | EVAN [15,16][13][14] (NCT01683175) | II | NCT03983811 | III | 174 | NeoADAURAOct 2021 | [28][102 | 262012–2015 | 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) |
(NCT04351555) |
ALNEO [36] | 84.2 vs. 61.1 m | (HR 0.32, 95% CI 0.15–0.67) | ||||||||||||||||
[ | IIB-IIIA | 34III | 328 | Mar 2024 | II-IIIB N2Icotinib/placebo on days 8–15 during adj q21 CT cycles, then × 2 y |
DFS | EVIDENCE | |||||||||||
Neoadj osimertinib + CT × 3 cycles vs. placebo + CT vs. osimertinib alone (1:1:1) | [17][15] (NCT02448797) | III | 322 | 2015–2019 | CORINII-IIIA | (NCT02264210)Icotinib × 2 y |
80 a vs. adj CT (1:1) |
47.0 vs. 22.1 m |
II | Mar 2023(HR 0.36, 95% CI 0.24–0.55, p < 0.0001) | Not reached (HR 0.91, 95% CI 0.42–1.94) |
|||||||
128 | Dec 2025 | IB | Icotinib × 12 m vs. observation | IB-III | DFS | Neoadj alectinib × 8 w, then adj CT and alectinib × 2 y |
MPR | ADAURA [18,[1619]][17] (NCT02511106) | III | |||||||||
NCT01746251 | 682 | 2015–2019 | IB-IIIA | Osimertinib × 3 y | II 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 |
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 |
Clinical Trial | Phase | N° pts | Estimated Primary Completion | Stage | Treatment Arms | Primary Endpoint |
---|---|---|---|---|---|---|
MPR | ||||||
] |
(NCT05015010) | |||
II | |||
33 | |||
May 2023 | III | Neoadj alectinib × 8 w, then adj × 96 w after surgery | MPR |
NAUTIKA1 (NCT04302025) | II |