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Lung adenocarcinoma — early-stage and perioperative therapy

TL;DR — Curative-intent adenocarcinoma care requires invasive nodal staging when indicated, anatomic and physiologic assessment, complete resection or definitive radiation, and stage- plus genotype-aware systemic therapy. In small peripheral node-negative NSCLC, randomized trials support segmentectomy or sublobar resection under strict staging and margin conditions, not indiscriminate wedge resection (Saji 2022, PMID 35461558; Altorki 2023, PMID 36780674). Cisplatin-based adjuvant chemotherapy produces an approximately 5.4 percentage-point five-year survival benefit across resected NSCLC, while ADAURA and ALINA created genotype-specific postoperative pathways for EGFR- and ALK-positive disease (Pignon 2008, PMID 18506026; Wu 2020, PMID 32955177; Tsuboi 2023, PMID 37272535; Wu 2024, PMID 38598794). For driver-negative resectable disease, neoadjuvant or perioperative chemo-immunotherapy improves event-free survival and pathologic complete response, but trials have not isolated the marginal value of the postoperative checkpoint component (Forde 2022, PMID 35403841; Wakelee 2023, PMID 37272513; Heymach 2023, PMID 37870974). ctDNA/MRD is strongly prognostic but remains investigational for withholding or escalating standard therapy.

Curative-intent pathway

Step Decision Failure prevented
1 Confirm invasive adenocarcinoma and stage using the current TNM edition Treating a metastasis or understaged N2/N3 disease as local
2 Brain imaging and PET/CT as stage/risk indicate Missing distant disease before thoracotomy
3 EBUS/EUS or mediastinoscopy when nodes are suspicious or risk is material Unexpected multistation nodal disease
4 Assess FEV1, DLCO, postoperative reserve, exercise capacity, and comorbidity Choosing an operation the patient cannot physiologically tolerate
5 Obtain broad molecular testing and PD-L1 when perioperative systemic choice depends on them Giving immunotherapy to EGFR/ALK-driven disease before genotype
6 Multidisciplinary sequence decision Losing resectability or duplicating modalities
7 Pathology review: margins, nodes, patterns, STAS, grade, actionable genotype Incomplete postoperative risk definition

Ninth-edition TNM changed N and M subdivisions and stage groups; every comparative series should state which edition was used (Rami-Porta 2024, PMID 38447919; Detterbeck 2024, PMID 38885896).

Surgery and extent of resection

Lobectomy with systematic nodal assessment remains the benchmark for a fit patient with resectable disease not meeting evidence-based criteria for lesser resection. Physiologic candidacy integrates predicted postoperative FEV1/DLCO and exercise performance, not age alone (Brunelli 2009, PMID 19477657).

Trial Population Comparison Result Boundary
JCOG0802/WJOG4607L Peripheral clinical stage IA, ≤2 cm, consolidation-to-tumor ratio >0.5 Segmentectomy vs lobectomy OS favored segmentectomy; local relapse higher Japanese, small peripheral tumors; anatomical segmentectomy (PMID 35461558)
CALGB/Alliance 140503 Peripheral cT1aN0 NSCLC ≤2 cm with intraoperative node confirmation Sublobar vs lobar resection DFS noninferior; OS similar Trial-quality node assessment and margins required (PMID 36780674)

Adenocarcinoma pattern matters. AIS and MIA have near-zero recurrence after complete resection in well-characterized cohorts, whereas micropapillary/solid patterns and spread through air spaces (STAS) associate with recurrence (Yotsukura 2021, PMID 33915249; Chen 2019, PMID 30914285).

Frozen-section classification is imperfect. A low-risk radiographic lesion should not be assumed AIS/MIA until the entire tumor is sampled; invasive foci, STAS, and complex glandular patterns can be missed.

SABR and nonsurgical local therapy

Stereotactic ablative radiotherapy is a curative-intent standard for medically inoperable stage-I NSCLC and an option when an operable patient declines surgery after informed comparison. The absence of surgical pathology leaves nodal and molecular uncertainty, while central location, interstitial lung disease, and proximity to critical structures alter risk.

Comparisons of surgery and SABR outside randomized trials are strongly confounded by operability and comorbidity. Small under-accrued randomized studies cannot settle equivalence for fit surgical candidates.

Adding checkpoint therapy to SABR has now failed in two phase 3 trials. SWOG/NRG S1914 (NCT04214262) randomized 417 patients with high-risk, medically inoperable or surgery-declining T1–3N0 NSCLC to SABR with or without induction, concurrent, and consolidation atezolizumab; accrual closed for futility, the OS HR was 1.04 (95% CI 0.69–1.58), 2-year OS was 82% in both arms, and grade ≥3 adverse events were 12% versus 3% with two grade 5 respiratory events in the atezolizumab arm (Daly 2026, PMID 42702214). KEYNOTE-867 (NCT03924869) randomized 448 patients with inoperable or surgery-refusing stage I–II (T1 to limited T3, N0) NSCLC to SBRT plus pembrolizumab or SBRT plus placebo: median EFS 31.2 versus 28.3 months, HR 0.92 (0.69–1.24), grade 3–5 treatment-related events 20.4% versus 3.7%, and five treatment-related deaths, all on pembrolizumab; the trial was stopped early (Jabbour 2026, PMID 42950173).

Adjuvant platinum chemotherapy

The LACE individual-patient meta-analysis found a death HR of 0.89 (95% CI 0.82–0.96), corresponding to a 5.4% absolute five-year survival gain for cisplatin-based adjuvant chemotherapy. Stage-specific HRs were 1.40 in IA, 0.93 in IB, 0.83 in II, and 0.83 in III (Pignon 2008, PMID 18506026).

The estimate predates routine targeted and immune therapy. Current decisions must avoid double counting benefit when combining treatments supported by trials with differing chemotherapy requirements, stages, and biomarker exclusions.

Adjuvant targeted therapy

EGFR: ADAURA

ADAURA randomized completely resected stage IB–IIIA EGFR exon-19-deletion/L858R NSCLC to osimertinib or placebo for three years after optional chemotherapy. Initial DFS HR was 0.17 in stage II–IIIA and 0.20 overall (Wu 2020, PMID 32955177). Mature OS analysis reported death HR 0.49 and five-year OS 88% versus 78% in stage IB–IIIA (Tsuboi 2023, PMID 37272535).

A post hoc 8-year landmark update reported OS HR 0.52 and 8-year OS 79% versus 64% in stage IB–IIIA, with 127 of 558 patients alive at the earlier cutoff not followed further (Wu 2026, PMID 42732874). ICWIP (three years of icotinib after adjuvant chemotherapy, n=135) improved DFS (HR 0.54) without a detectable OS difference (Liu 2026, PMID 42660909).

The trials establish benefit, not the optimal duration, ctDNA-guided selection, or the best therapy after relapse following three years of osimertinib.

ALK: ALINA

ALINA compared two years of alectinib with four cycles of platinum chemotherapy after complete resection of stage IB–IIIA ALK-positive NSCLC. Disease-free survival, including CNS outcomes, strongly favored alectinib (Wu 2024, PMID 38598794).

Because the control was chemotherapy rather than chemotherapy followed by alectinib, the trial answers a practical regimen comparison but leaves the additive value of chemotherapy and mature overall survival unresolved. The safety and quality-of-life report found fewer discontinuations for adverse events with alectinib (5% vs 13%) and SF-36 physical and mental scores near population norms over two years of treatment (Dziadziuszko 2026, PMID 42636834).

ELEVATE (NCT05341583) randomized 274 patients with completely resected stage IB–IIIB ALK-positive NSCLC, after adjuvant chemotherapy, to two years of ensartinib or placebo. In stage II–IIIB, 24-month DFS was 86.4% versus 53.5% (HR 0.20); overall-population DFS HR was also 0.20; OS was immature; grade ≥3 adverse events were 35.8% versus 18.2%, most commonly rash (Yue 2026, PMID 42418775). ELEVATE therefore tests adjuvant ALK inhibition after chemotherapy against placebo, whereas ALINA tests alectinib against chemotherapy. Neither trial isolates chemotherapy-plus-alectinib from alectinib alone.

Neoadjuvant and perioperative immunotherapy

Trial Architecture Efficacy Safety/interpretation
CheckMate 816 3 cycles nivolumab + chemotherapy vs chemotherapy; no mandated adjuvant IO EFS 31.6 vs 20.8 mo, HR 0.63; pCR 24.0% vs 2.2% Surgery 83.2% vs 75.4%; grade 3–4 treatment-related AE 33.5% vs 36.9% (PMID 35403841)
KEYNOTE-671 Neoadjuvant pembrolizumab-chemo, surgery, adjuvant pembrolizumab 24-mo EFS 62.4% vs 40.6%, HR 0.58; pCR 18.1% vs 4.0% Cannot isolate postoperative component (PMID 37272513)
AEGEAN Neoadjuvant durvalumab-chemo, surgery, adjuvant durvalumab EFS HR 0.68; pCR 17.2% vs 4.3%; second interim EFS HR 0.69, interim OS HR 0.89 (95% CI 0.70–1.14) (PMID 42664473) Known EGFR/ALK excluded from efficacy analysis (PMID 37870974); OS not yet significant
CheckMate 77T Neoadjuvant nivolumab-chemo, surgery, adjuvant nivolumab Improved EFS and pathologic response Perioperative architecture; marginal adjuvant effect unknown (PMID 38749033)

Pathologic complete response is a strong individual prognostic marker but is not yet a fully validated treatment-switch surrogate. A patient without pCR may still be cured; a patient with pCR may still relapse. In the CheckMate 77T biomarker subset (41% of randomized patients), pre-surgical ctDNA clearance occurred in 66% with nivolumab versus 38% with placebo, and every MRD-negative patient who became ctDNA-positive during the adjuvant period recurred (Cascone 2026, PMID 42587156).

Driver-positive tumors need separate reasoning. EGFR/ALK disease was excluded or uncommon in pivotal perioperative immune analyses, and the availability of adjuvant osimertinib or alectinib changes the risk-benefit calculation.

Adjuvant immunotherapy

IMpower010 tested atezolizumab after platinum chemotherapy. DFS improved most clearly in stage II–IIIA disease with tumor-cell PD-L1 ≥1% (HR 0.66), while effect estimates attenuated in broader populations (Felip 2021, PMID 34555333).

PEARLS/KEYNOTE-091 found a DFS benefit for adjuvant pembrolizumab in the overall population but not a statistically significant benefit in the prespecified PD-L1 ≥50% group at interim analysis (O'Brien 2022, PMID 36108662). The discordance warns against assuming metastatic PD-L1 rules transfer unchanged to resected disease. A systematic review reconstructing Kaplan-Meier curves from four postoperative PD-1/PD-L1 trial families (4,336 participants) estimated 36-month restricted-mean DFS gains of 1.3–2.0 months, equivalent to 2.3–6.1 additional patients per 100 without a DFS event, with intervals crossing zero for several estimates and exploratory OS intervals compatible with benefit or harm (Yao 2026, PMID 42843316).

Unresectable stage III disease

Concurrent platinum chemoradiotherapy followed by durvalumab is supported by PACIFIC. Five-year OS was 42.9% with durvalumab versus 33.4% with placebo, with PFS 33.1% versus 19.0% (Antonia 2017, PMID 28885881; Spigel 2022, PMID 35108059).

R-ALPS (NCT04325763), a Chinese double-blind phase 3 trial, randomized 553 patients without progression after concurrent or sequential chemoradiotherapy to benmelstobart plus anlotinib, benmelstobart, or placebo. In stage 1, median PFS was 15.1, 9.7, and 4.2 months (HR 0.49 and 0.53 versus placebo). Adding anlotinib did not significantly improve PFS versus benmelstobart alone (pooled HR 0.82, 95% CI 0.63–1.08) and increased grade 3–5 treatment-related events (48.8% vs 29.4% vs 19.7%), including grade 5 events 7.2% versus 1.4% versus 1.5% (Ji 2026, PMID 42955021). The population was 89.5% male; the control was placebo, not durvalumab; the ClinicalTrials.gov record is listed UNKNOWN (last update 2022-03-31). This is a China-only consolidation signal, not a PACIFIC replacement.

For EGFR-mutant unresectable stage III disease, consolidation should not be inferred from the largely unselected PACIFIC population. LAURA randomized 216 patients without progression after chemoradiotherapy to osimertinib or placebo: PFS 39.1 versus 5.6 months, HR 0.16 (Lu 2024, PMID 38828946). At the second interim OS analysis (31% maturity) the OS HR was 0.67 (95% CI 0.40–1.14), and PFS2 HR 0.62 (0.35–1.08); osimertinib was the first subsequent therapy for 50 of the 66 patients (76%) who discontinued placebo, which limits OS separation (Özgüroğlu 2026, PMID 42714840). The Chinese ADVANCE trial (ChiCTR2000040590) compared aumolertinib plus radiotherapy with cisplatin-pemetrexed chemoradiotherapy but stopped after 43 of a planned 98 patients; PFS was 34.0 versus 7.4 months (HR 0.15) (Bi 2026, PMID 42764281). The WHO ICTRP record for ChiCTR2000040590, retrieved 2026-10-16, still lists recruitment as "Pending".

ctDNA and molecular residual disease

Tumor-informed ctDNA after curative-intent treatment can identify molecular relapse months before imaging in some patients (Chaudhuri 2017, PMID 28899864; Abbosh 2017, PMID 28445469).

Use Evidence status Why it is not yet routine replacement for pathology/stage
Postoperative prognosis Strong association with recurrence Sensitivity is limited in low-shedding, small, and CNS-only disease
Early relapse detection Lead time shown No proof that earlier treatment improves survival
Adjuvant escalation Interventional trials ongoing Positive predictive value and effective rescue regimen both matter
De-escalation Attractive for toxicity reduction False-negative MRD could deny curative therapy
Treatment monitoring Dynamic signal Assay, sampling time, and clonal hematopoiesis affect interpretation

Prospective cohorts support prognostic value (LUNGCA-1, PMID 34844976; dynamic recurrence analysis, PMID 34799585), but utility requires randomized evidence that acting on the result improves outcomes. Two 2026 analyses extend the prognostic evidence without supplying that randomization. In the EVIDENCE phase 3 trial of adjuvant icotinib versus chemotherapy (175 patients, 1,352 plasma samples), landmark MRD positivity carried DFS HR 4.44 and longitudinal monitoring had a 91.3% negative predictive value with 169 days' median lead time (Zhou 2026, PMID 42706268). In unresectable stage III disease treated with chemoradiotherapy and durvalumab (84 patients), ctDNA detected after six months of durvalumab or three months after completion predicted progression, whereas ctDNA after chemoradiotherapy but before durvalumab did not (Horndalsveen 2026, PMID 42336205).

Surveillance and recurrence

Surveillance must detect recurrence, new primary lung cancers, treatment toxicity, and functional decline. CT schedules should be documented rather than assumed. Routine brain imaging in asymptomatic resected patients is not uniformly recommended; genotype and recurrence pattern may motivate research questions but do not replace guideline review.

Open questions

  • What is the marginal value of adjuvant checkpoint therapy after neoadjuvant chemo-IO and complete resection, given small reconstructed absolute DFS gains for postoperative blockade (PMID 42843316) and AEGEAN's non-significant interim OS (PMID 42664473)?
  • Can ctDNA safely omit chemotherapy or shorten three years of adjuvant osimertinib (PMIDs: 32955177, 28899864)?
  • Does adjuvant targeted therapy increase cure fraction or postpone relapse, and how should post-adjuvant relapse be treated?
  • Which high-grade histologic patterns independently justify escalation after stage and genotype are known?
  • Which operable patients obtain better quality-adjusted survival from SABR than surgery?
  • How should resectable N2 disease be divided between surgery-containing and definitive chemoradiation pathways?

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