Table Info

Table 1.

Selected phase III trials

Trial	Number of patients/characteristics	Intervention	Histologies (SCC/adeno)	Results	Main conclusion of the study
CRT followed by surgery vs. definitive RT
NCT00002550, 2009 [10]	N = 429 pts Stage IIIA (T1–3, pN2) Stage IIIB excluded	Arm 1: CRT and surgery Arm 2: CRT and definitive RT CT (cis-etoposide)	30%/38%	5-year PFS 22.4% (arm 1) vs. 11.1% mOS 23.6 months (arm 1) vs. 22.2 months, HR: 0.87, NS	No significant survival advantage of surgery compared to RT-CT
Induction CT, RT-CT followed by surgery vs. RT-CT
ESPATUE, 2015 [11]	N = 161 pts, potentially resectable Stage IIIA (34%) Stage IIIB (65%) TNM 6th	Induction CT (×3 cis-paclitaxel) followed by CRT (cis-vinorelbin) and if resectable: CRT vs. surgery (arm1/2)	39%/47%	No difference in 5-year OS or PFS	No significant survival advantage of adding surgery to CT and RT-CT, but underpowered trial
CT before and after RT
PROCLAIM, 2016 [16]	N = 598 pts, unresectable Stage IIIA (47%) Stage IIIB (52%) TNM 6th	Arm 1: CT (cis-pem) ×3 + TRT followed by pem ×4 Arm 2: CT (cis-etoposide) ×2 + TRT followed by platinum-based CT	-/75%	No difference in OS	Cis-etoposide or cis-pem can be considered with concomitant RT for adenocarcinoma
Adjuvant immunotherapy post-RT-CT
PACIFIC, 2022 [17, 18]	N = 713 pts, unresectable Stage IIIA (53%) Stage IIIB (44%)	Durvalumab vs. placebo after ≥ 2 cycles of CRT without progression, for 12 months	46%/54%	5-year OS 42.9% for durvalumab vs. 33.4%, HR: 0.72 5-year PFS 33.1% vs. 19%, HR: 0.55	Significant improvement in OS/PFS with durvalumab post CRT
Adjuvant immunotherapy
IMpower010, 2023 [26]	N = 1,005 pts, completely resected Stage II (52%) Stage IIIA (48%) PD-L1 ≥ 50% (23%) TNM 7th Adjuvant platinum-based CT	Adjuvant: atezolizumab for 1 year vs. BSC	40%/48%	mOS not estimable in ITT population, but trend shown in PD-L1 ≥ 50%, HR: 0.43	Significant improvement in DFS with atezolizumab post-surgery, regardless of PD-L1 status
PEARLS/Keynote-091, 2022 [25]	N = 1178 pts, completely resected Stade IB (14%), stage II (57%), stage IIIA (29%) TNM 7th PD-L1 TPS < 1% (39%), 1–49% (32%), ≥ 50% (28%) Adjuvant CT mandatory for stage II/IIIA	Adjuvant: pembrolizumab vs. placebo for 1 year	35%/64%	mDFS 53.6 months for pembrolizumab group vs. 42 months, HR: 0.76 mOS not reached in either group	Improvement of DFS with adjuvant pembrolizumab regardless of PD-L1 expression No requirement for EGFR/ALK testing (limitation)
Adjuvant targeted therapies
ADAURA, 2023 [41, 42]	N = 682 pts, completely resected, EGFR positive Stage IB (32%), II (34%), IIIA (35%) Adjuvant CT recommended for stage II–IIIA	Osimertinib adjuvant for 3 years vs. placebo	-/97%	5-year OS 88% in the osimertimib group vs. 78%, HR: 0.49	Adjuvant osimertinib improves DFS and OS compared to placebo, in resected EGFR mutated NSCLC
ALINA, 2023 [44]	N = 257 pts, completely resected, ALK positive Stage IB–IIIA	Alectinib adjuvant for 2 years vs. CT	NA	mDFS: NR vs. 44.4 months in stage II–IIIA, HR: 0.24	Adjuvant alectinib improves DFS compared to adjuvant platinum-based CT, in resected EGFR mutated NSCLC
Neo-adjuvant CT-immunotherapy
CheckMate-816, 2022 [30]	N = 773 pts, resectable Stage IB or II (35%) Stage IIIA (64%) TNM 7th PD-L1 < 1% (43%), 1–49% (27%), ≥ 50% (22%)	Platinum-based CT +/– nivolumab ×3, followed by surgery	50%/49%	mEFS 31.6 months in nivolumab group vs. 20.8 months, HR: 0.63 pCR: 24% in the nivolumab group vs. 2.2%	Significant improvement in EFS and pCR with neoadjuvant CT + nivolumab No higher incidence/greater severity of AE with nivolumab
Perioperative CT-immunotherapy
Keynote-671, 2023 [32, 33]	N = 797 pts, resectable Stage II–IIIB	Cis-based CT + pembrolizumab vs. placebo for 4 neoadjuvant cycles, followed by surgery and adjuvant pembrolizumab vs. placebo for 1 year	NA	36-months EFS 54.3% in the pembrolizumab group vs. 35.4% 36-months OS 71.3% vs. 64%, HR 0.72. pCR 18.1% vs. 4%	Perioperative pembrolizumab improves OS, EFS and pathological response
CheckMate-77T, 2023 [31]	N = 461 pts, resectable Stage II–IIIB	Platinum-based CT + nivolumab vs. placebo for 4 neoadjuvant cycles, followed by surgery and adjuvant nivolumab vs. placebo for 1 year	51%/49%	mEFS NR vs. 18.4 months, HR: 0.58 pCR 25.3% vs. 4.7% MPR 35.4% vs. 12.1%	Perioperative immunotherapy improves EFS and pathological response
AEGEAN, 2023 [34, 35]	N = 802 pts, resectable Stage II–IIIB	Platinum-based CT + durvalumab vs. placebo for 4 neoadjuvant cycles, followed by surgery and adjuvant durvalumab vs. placebo for 1 year	46.2%/53%	mEFS in mITT: NR vs. 25.9 months. HR: 0.68 pCR: 17.2% vs. 4.3%. Difference in pCR: 13.0%	Perioperative immunotherapy improves EFS and pathological response
NEOTORCH, 2023 [36]	N = 404 pts, resectable Stage III	Platinum-based CT + toripalimab or placebo for 3 neoadjuvant cycles Followed by surgery and platinum-based CT + toripalimab or placebo for 1 adjuvant cycles Followed by toripalimab vs. placebo) for 12 adjuvant cycles	77%/32%	mEFS: NR vs. 15.1 months. HR: 0.40 MPR 48.5% vs. 8.4%	Perioperative immunotherapy improves EFS and pathological response

CRT: chemo-RT; CT: chemotherapy; Adeno: adenocarcinoma; SCC: squamous cell carcinoma; AE: adverse event; BSC: best supportive care; Cis: cisplatin; EFS: event-free survival; HR: hazard ratio; NS: not significative; nSCC: non-squamous cell carcinoma; OS: overall survival; pCR: pathological complete response; Pem: pemetrexed; PFS: progression-free survival; pts: patients; TRT: thoracic radiation therapy; DFS: disease-free survival; MPR: major pathological response; PD-L1: programmed cell death ligand-1; EGFR: epidermal growth factor receptor; ALK: anaplastic lymphoma kinase; mDFS: median disease-free survival; pN2: pathologic N2 stage; mOS: median overall survival; mEFS: median event-free survival; NR: not reported; ITT: intention to treat; mITT: modified intention to treat; TPS: tissue proportion score; NA: not available; + or –: with or without

Declarations

Author contributions

FK and MB: Writing—original draft. AA: Writing—review & editing. AF: Supervision, Writing—review & editing, Conceptualization. All authors approved the final version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

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