Lung adenocarcinoma — open questions¶
Last curated: 2026-08-29
Use. Tier 1 questions could change practice and can be tested with a feasible contemporary design. Tier 2 questions need assay, cohort, endpoint, or mechanistic development before a definitive practice-changing trial. IDs are stable; retire an ID rather than renumbering it.
Tier 1 — practice-changing and designable now¶
OQ-1 — Who needs first-line EGFR intensification?¶
Question. In untreated EGFR exon-19-deletion/L858R metastatic disease, which prespecified baseline clinical/genomic state identifies an OS or quality-adjusted-survival advantage from osimertinib plus chemotherapy or amivantamab-lazertinib over osimertinib alone?
Why open. Intensification improves PFS but adds cytotoxic or infusion/VTE/skin burden; no validated selector defines who needs it (FLAURA PMIDs: 29151359, 31751012; FLAURA2 PMID 37937763; MARIPOSA PMID 38924756).
OQ-2 — Can adjuvant osimertinib duration be individualized?¶
Question. Does tumor-informed ctDNA plus pathologic risk safely identify patients for shorter versus longer adjuvant osimertinib?
Why open. ADAURA used three years and improved OS, while postoperative ctDNA is prognostic but not yet treatment-directive (PMIDs: 32955177, 37272535, 28899864, 34844976).
OQ-3 — What is the optimal post-adjuvant EGFR strategy?¶
Question. At relapse after adjuvant osimertinib, should treatment depend on time off drug, resistance genotype, disease site, or re-challenge response?
Why open. Metastatic resistance data largely arise after continuous first-line therapy, not the postoperative stop–relapse state (PMIDs: 32483558, 38871738).
OQ-4 — Alectinib alone or chemotherapy plus alectinib after resection?¶
Question. In resected ALK-positive stage II–IIIA NSCLC, does adding platinum chemotherapy to adjuvant alectinib improve cure enough to justify toxicity?
Why open. ALINA compared alectinib with chemotherapy, not chemotherapy followed by alectinib, and mature OS is pending (PMID 38598794).
OQ-5 — Which ALK first-line lifetime sequence is best?¶
Question. Does first-line lorlatinib yield better lifetime CNS control, neurocognitive quality, and post-resistance survival than alectinib followed by genotype-directed later therapy?
Why open. ALEX and CROWN establish superiority to crizotinib but do not compare modern sequences head to head (PMIDs: 28586279, 33207094, 34139965).
OQ-6 — When can radiation be deferred for brain metastases?¶
Question. In asymptomatic measurable CNS disease with a targetable driver, does upfront CNS-active TKI with prespecified MRI rescue preserve neurocognition without compromising intracranial control versus immediate stereotactic radiation plus TKI?
Why open. CNS activity is strong for multiple TKIs, while symptomatic brain metastases still require local therapy; randomized deferral evidence is sparse (PMIDs: 30215676, 31838015, 38197815, 34932393).
OQ-7 — What should follow modern ROS1 inhibitors?¶
Question. Can prospective paired tissue/plasma genotyping allocate therapy after repotrectinib or entrectinib according to solvent-front, compound, and bypass resistance?
Why open. TRIDENT-1 addresses important earlier states, but post-new-generation resistance is heterogeneous and lacks a validated sequence (PMID 38197815).
OQ-8 — Can KRAS G12C move first line safely?¶
Question. Which KRAS G12C inhibitor combination improves OS over standard PD-L1-directed chemo-immunotherapy without excess hepatic, immune, or gastrointestinal toxicity?
Why open. Current randomized evidence is later-line with modest PFS benefit; first-line combinations are active in registries (PMIDs: 36764316, 35658005; NCT06793215 verified 2026-08-29).
OQ-9 — Are STK11 and KEAP1 predictive?¶
Question. In a biomarker-stratified randomized trial, do STK11 and/or biallelic KEAP1 states identify differential benefit from a specific chemo-immune or investigational regimen?
Why open. They associate with poor immune outcomes, and POSEIDON subgroup/translational evidence supports CTLA-4-containing chemo-immunotherapy as a resistance-mitigating strategy; dedicated prospective biomarker selection and independent validation remain incomplete (PMIDs: 29773717, 34740862, 32866624, 36526124, 39385035).
OQ-10 — HER2 TKI versus ADC sequence¶
Question. In HER2-mutant metastatic disease, should a HER2-selective TKI precede T-DXd to maximize CNS control and reduce cumulative ILD risk?
Why open. T-DXd has high response with clinically important ILD; zongertinib introduces an oral, mutation-selective alternative without randomized sequencing data (PMIDs: 34534430, 37694347, 40293180).
OQ-11 — Can MET resistance guide inhibitor class switching?¶
Question. Does prospective structural classification of D1228/Y1230 and bypass resistance improve outcomes from type-I/type-II MET inhibitor sequencing?
Why open. Preclinical sensitivity patterns exist, but capmatinib/tepotinib resistance has no validated routine sequence (PMIDs: 32877583, 32469185, 35690785).
OQ-12 — Is postoperative checkpoint therapy necessary?¶
Question. After neoadjuvant chemo-immunotherapy and complete resection, can patients with pCR and/or ctDNA clearance omit adjuvant checkpoint therapy without worse EFS/OS?
Why open. CheckMate 816 used neoadjuvant-only therapy, whereas KEYNOTE-671, AEGEAN, and CheckMate 77T combine pre- and postoperative therapy; cross-trial comparison cannot isolate the adjuvant component (PMIDs: 35403841, 37272513, 37870974, 38749033).
OQ-13 — Can MRD improve cure rather than prediction?¶
Question. Does ctDNA-triggered adjuvant escalation improve OS, or ctDNA-negative de-escalation preserve OS while reducing toxicity, versus stage/genotype-guided standard care?
Why open. Multiple cohorts establish recurrence prediction. A live PubMed search on 2026-08-29 found randomized intervention protocols in resected EGFR-mutant and advanced immunotherapy settings, but no mature randomized action result establishing survival utility (cohort PMIDs: 28899864, 28445469, 34844976, 34799585; protocol PMIDs: 39659920, 41628935).
OQ-14 — Which never-smokers should receive LDCT?¶
Question. Can a risk model using age, family history, ancestry, air pollution, lung disease, and germline factors identify a never-smoker population with favorable mortality benefit, false-positive procedure burden, and overdiagnosis?
Why open. TALENT shows detection yield without randomized mortality benefit; smoking-based policies exclude never-smokers (PMIDs: 38042167, 33687470, 40604281).
OQ-15 — Which screening selector improves equity?¶
Question. Does risk-model eligibility outperform categorical age/pack-year rules for deaths prevented per scan without worsening racial, sex, rural, or socioeconomic inequity?
Why open. Modelling favors risk-based strategies under some assumptions, while implementation disparities persist (PMIDs: 36745885, 37806735, 42038935).
OQ-16 — What is the best post-chemo-IO sequence?¶
Question. In driver-negative adenocarcinoma progressing after platinum-pemetrexed-checkpoint therapy, which biomarker-defined second-line strategy improves OS and patient-reported function versus docetaxel-based care?
Why open. First-line evidence is strong; post-combination resistance lacks a universal randomized sequence (KEYNOTE-189, PMID 29658856).
OQ-17 — Can oligoprogression be trial-defined?¶
Question. Does ablation of all progressing sites with continuation of an otherwise effective TKI improve time to next systemic therapy and OS versus immediate switching, stratified by driver and ctDNA state?
Why open. Small randomized oligometastatic trials predate modern driver-specific therapy and did not define molecular oligoprogression (PMIDs: 31067138, 28973074).
OQ-18 — How should frail patients be treated?¶
Question. In ECOG 2–3 or geriatric-vulnerable adenocarcinoma, which attenuated targeted, immune, or chemotherapy strategies preserve function and survival?
Why open. Pivotal systemic trials largely enrolled performance status 0–1, leaving major transportability uncertainty (PMIDs: 29658856, 27718847).
Tier 2 — enabling science and design work needed¶
OQ-19 — What initiates never-smoker adenocarcinoma?¶
Question. Which geographically varying mutational signatures correspond to causal, modifiable exposures rather than correlated geography or endogenous processes?
Why open. Sherlock-Lung maps signatures and driver differences, while PM2.5 experiments support a promoter mechanism; individual exposure attribution remains unresolved (PMIDs: 40604281, 37020004).
OQ-20 — Can pollution prevention reduce EGFR-driven incidence?¶
Question. Does sustained PM2.5 reduction lower EGFR-mutant adenocarcinoma incidence on a measurable lag, and through which inflammatory intermediates?
Why open. Epidemiology and IL-1β-dependent experimental promotion are aligned but intervention evidence is absent (PMIDs: 24911630, 37020004).
OQ-21 — What does histologic grade add after genomics?¶
Question. Does IASLC grade improve calibrated recurrence prediction beyond TNM, driver/co-mutation state, radiology, and ctDNA enough to change adjuvant treatment?
Why open. Grade is prognostic in validation/meta-analysis, but prospective treatment interaction is not established (PMIDs: 33905897, 38485464).
OQ-22 — Is STAS biological or partly artifactual?¶
Question. Which standardized fixation, sectioning, and imaging rules distinguish true STAS from specimen artifact, and does a prospective STAS rule alter optimal resection extent?
Why open. STAS is prognostic but remains a descriptor rather than a TNM determinant (PMIDs: 30914285, 38508515).
OQ-23 — How much tumor must be sampled?¶
Question. What combination of multiregion tissue and plasma captures clinically actionable heterogeneity at diagnosis and progression without impractical biopsy burden?
Why open. TRACERx and mixed-response work show branched evolution and lesion discordance (PMIDs: 37046096, 38871738).
OQ-24 — Can spatial states become clinical assays?¶
Question. Can single-cell/spatial immune and stromal states be reduced to a locked, reproducible assay that improves treatment allocation beyond PD-L1 and genotype?
Why open. Atlases reveal rich cellular states but lack decision-utility validation (PMIDs: 28475900, 33972311, 41057692).
OQ-25 — What is a clinically meaningful plasma clone?¶
Question. Which variant-allele-frequency, error-model, and longitudinal rules separate actionable subclonal resistance from noise and clonal hematopoiesis?
Why open. Plasma complements tissue but low shedding and non-tumor variants complicate thresholds (PMIDs: 30988079, 34246791).
OQ-26 — Can AI improve a real pathology decision?¶
Question. Does an externally calibrated AI grading system improve interobserver agreement and treatment decisions, not only retrospective discrimination?
Why open. ANORAK and imaging classifiers report promising performance without prospective utility trials (PMIDs: 38200244, 37805451).
OQ-27 — Which biomarker captures productive immunity?¶
Question. Can antigen clonality, HLA competence, spatial T-cell state, and myeloid exclusion be combined into a robust selector outperforming PD-L1?
Why open. PD-L1 is clinically useful but incomplete; TMB and co-mutations show discordant immune biology (PMIDs: 27718847, 34648948, 32866624).
OQ-28 — How should chronic targeted-therapy survivorship be measured?¶
Question. Which longitudinal outcome set captures symptoms, cognition, work, adherence, caregiver burden, financial toxicity, and scan anxiety across driver groups?
Why open. Existing PRO and survivorship studies are broad lung-cancer cohorts and underdescribe years of oral therapy (PMIDs: 29110842, 22134070, 33555936).
OQ-29 — Can stigma interventions change behavior?¶
Question. Which clinician, media, and peer interventions reduce validated stigma scores and improve help-seeking, communication, trial discussion, or support use?
Why open. Stigma is measurable and associated with depression/delay, but intervention evidence is limited (PMIDs: 32721137, 30779396, 24769603).
OQ-30 — How should trial access be measured?¶
Question. Can molecular trials report a common screened → molecularly eligible → offered → consented → treated → retained cascade with patient time and travel burden?
Why open. Eligibility, referral, site, rural, and logistical barriers are repeatedly documented but denominators differ (PMIDs: 18650170, 22591607, 35451964).
Dots not yet connected¶
These are cross-domain junctions where both evidence bodies exist in this knowledge base but no completed study has joined them sufficiently to guide practice.
| # | Dot A | Dot B | The missing junction | Powers |
|---|---|---|---|---|
| D1 | Never-smoker geographic signatures (PMID 40604281) | Pack-year screening rules (PMID 33687470) | Prospective signature/exposure-informed risk selection with mortality endpoint | OQ-14, OQ-19 |
| D2 | PM2.5-driven clonal promotion (PMID 37020004) | EGFR-mutant incidence and prevention policy | Natural experiment linking pollution reduction to molecularly typed incidence | OQ-20 |
| D3 | IASLC grade/STAS prognosis (PMIDs: 38485464, 38508515) | Adjuvant targeted/immune therapy | Treatment-by-morphology interaction after genotype and stage | OQ-21, OQ-22 |
| D4 | Postoperative ctDNA prognosis (PMID 28899864) | ADAURA/ALINA duration (PMIDs: 37272535, 38598794) | MRD-randomized targeted-therapy duration | OQ-2, OQ-4, OQ-13 |
| D5 | CNS-active TKIs (PMIDs: 30215676, 38197815) | Neurocognitive cost of radiation | Randomized radiation-deferral design with CNS and cognition endpoints | OQ-6 |
| D6 | TRACERx spatial evolution (PMID 37046096) | Oligoprogression local therapy (PMID 31067138) | Molecularly defined local-ablation versus switch trial | OQ-17, OQ-23 |
| D7 | STK11/KEAP1 immune exclusion and POSEIDON CTLA-4 subgroup signal (PMIDs: 29773717, 32866624, 39385035) | First-line chemo-IO benefit (PMID 29658856) | Dedicated biomarker-randomized validation of the CTLA-4 interaction or another rescue strategy | OQ-9 |
| D8 | HER2-ADC ILD (PMID 34534430) | HER2-selective oral TKI activity (PMID 40293180) | Randomized sequence with CNS, ILD, and QoL endpoints | OQ-10 |
| D9 | Perioperative pCR/ctDNA (PMID 35403841) | Postoperative checkpoint exposure (PMIDs: 37272513, 37870974) | Response-adapted omission of adjuvant IO | OQ-12, OQ-13 |
| D10 | Plasma whole-body sampling (PMID 30988079) | Transformation requiring tissue | Prospective triage rule for plasma-only versus mandatory biopsy | OQ-23, OQ-25 |
| D11 | Chronic TKI survival | Financial/caregiver trajectories (PMIDs: 33555936, 29476636) | Driver-specific longitudinal survivorship cohort | OQ-28 |
| D12 | Molecular patient communities | Trial access attrition (PMIDs: 18650170, 22591607) | Patient-led decentralized trial design with full cascade reporting | OQ-30 |
Retirement rule¶
An OQ is retired only when a sufficiently direct study answers the decision, not when a related biomarker association or single-arm response appears. The retirement entry should preserve the old ID, answer date, key source, remaining boundary, and pages changed.