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Clinical-trials landscape¶
TL;DR¶
- The LUSC trial landscape has moved from unselected cytotoxic comparisons to perioperative immunotherapy, biomarker-defined metabolism, antibody–drug conjugates (ADCs), personalized vaccines, ctDNA-guided treatment, and duration/de-escalation questions.
- The most important negative lesson is structural: a recurrent genomic alteration, cell-surface protein, or encouraging response rate is not enough. LUSC repeatedly defeats programs through intratumour heterogeneity, non-oncogene dependence, toxicity, or failure to improve survival.
- Trial eligibility is a clinical decision. Histology, TNM edition, measurable disease, prior checkpoint therapy, molecular alteration, brain-metastasis status, organ function, autoimmune history, bleeding risk, and washout periods all matter.
- “Recruiting” is registry status, not a promise that a nearby site has an open slot. Contact information, cohort availability, geography, and last update must be rechecked on the day of referral.
- Completed landmark trials belong in the landscape because they explain current standards; active studies belong because they expose unresolved questions. They should never be mixed in one undifferentiated list.
- All registry identifiers and statuses below were fetched live from the ClinicalTrials.gov API v2 on 31 August 2026 and re-fetched on 10, 17 and 24 October 2026. Previously tracked records retained their most recently recorded overall status, enrollment, and results-posting flag. Last-update dates moved on NCT04310007 (2026-10-22; still restricted to non-squamous NSCLC) and NCT05456841 (2026-10-07; still recruiting). KEYNOTE-671 remains active, not recruiting. Two squamous-relevant registrations were added: first-line ABBV-1480 versus pembrolizumab plus chemotherapy ([NCT07756645](https://clinicaltrials.gov/study/NCT07756645){target="_blank" rel="noopener"}) and ctDNA-guided consolidation after chemoradiation ([NCT07858253](https://clinicaltrials.gov/study/NCT07858253){target="_blank" rel="noopener"}).
How this landscape was built¶
The registry was searched using squamous NSCLC, lung squamous carcinoma, Lung-MAP, NFE2L2/KEAP1, FGFR, and TROP2 concepts. Candidate records were then fetched individually by identifier. Registry fields can be sponsor-entered, delayed, incomplete, or changed after the access date. Published efficacy claims are linked to PubMed separately; a registry result posting is not assumed to equal peer-reviewed validation.
| Field | Interpretation rule |
|---|---|
| Overall status | Snapshot on access date; verify before referral |
| Phase | Development intent, not evidence quality by itself |
| Estimated enrollment | Planning number unless registry says actual |
| Primary outcome | Determines what the trial is powered or designed to answer |
| Histology | Read inclusion criteria; an “NSCLC” title may contain a dedicated squamous cohort or exclude it |
| Biomarker | Exact alteration, assay, expression threshold, and central confirmation matter |
| Intervention name | Mechanism hypothesis, not evidence of benefit |
| Country/site list | A listed site may not currently be open |
Standards established by completed or maturing phase III trials¶
These trials enrolled NSCLC except where the squamous population is explicit. LUSC subgroup consistency may support treatment, but subgroup absolute benefit and toxicity are not always fully reported.
Newly catalogued phase III report awaiting full-text synthesis¶
S1914 ([NCT04214262](https://clinicaltrials.gov/study/NCT04214262){target="_blank" rel="noopener"}) compares atezolizumab plus SBRT with SBRT in high-risk early-stage NSCLC. The live registry is active, not recruiting, with results posted; that administrative status is separate from publication. Daly et al.'s phase III report is catalogued ([PMID 42702214](https://pubmed.ncbi.nlm.nih.gov/42702214/){target="_blank" rel="noopener"}), but publisher access did not provide the article body. The registry outcome table and the publication abstract reflect different reported analyses; do not merge their estimates. Full-text and analysis-cutoff reconciliation is a next-sweep priority, not a new LUSC-specific efficacy estimate.
The platform-trial lesson¶
The original Lung-MAP master protocol was created specifically for previously treated advanced squamous lung cancer ([NCT02154490](https://clinicaltrials.gov/study/NCT02154490){target="_blank" rel="noopener"}); its registry status is completed. It matched patients to biomarker-defined substudies and allowed a non-match pathway. The platform demonstrated that nationwide molecular screening and modular substudies are feasible, while also documenting how often plausible targets fail to generate practice-changing efficacy ([PMID 25680375](https://pubmed.ncbi.nlm.nih.gov/25680375/){target="_blank" rel="noopener"}; [PMID 26408303](https://pubmed.ncbi.nlm.nih.gov/26408303/){target="_blank" rel="noopener"}).
| Platform advantage | Remaining problem |
|---|---|
| One screening architecture for multiple hypotheses | Screen-positive prevalence can be too low for timely accrual |
| Arms can open and close without rebuilding the whole network | Control standards change during the platform's life |
| Tissue and outcome data become reusable infrastructure | Tissue exhaustion and assay turnaround still exclude patients |
| Negative substudies are informative | Publication and interpretation can overemphasize small response signals |
| Histology focus exposes LUSC biology | Later expansion to all NSCLC can dilute histology-specific learning |
A search hit is not eligibility. Although [NCT04310007](https://clinicaltrials.gov/study/NCT04310007){target="_blank" rel="noopener"} has a generic NSCLC brief title and is Lung-MAP-related, its current record restricts eligibility to non-squamous NSCLC. It is therefore not an active LUSC option as of 24 October 2026.
Active LUSC-relevant studies by scientific question¶
Can maintenance be improved or shortened?¶
| Trial | Status; planned enrollment | Design signal | Primary question | Interpretation boundary |
|---|---|---|---|---|
| Cabozantinib + pembrolizumab maintenance ([NCT05613413](https://clinicaltrials.gov/study/NCT05613413){target="_blank" rel="noopener"}) | Recruiting; 36 estimated | Phase II pilot after platinum/taxane/pembrolizumab induction in metastatic squamous NSCLC | Median PFS | Small single-arm signal-seeking study; antiangiogenic bleeding and fistula risks matter in central LUSC |
| DIAL de-escalation ([NCT05255302](https://clinicaltrials.gov/study/NCT05255302){target="_blank" rel="noopener"}) | Recruiting; 1,360 estimated | Phase II/III duration study after disease control with chemo-immunotherapy | 18-month OS then OS | Lung-cancer-wide; asks whether maintenance exposure can be reduced, a patient-important toxicity/time question |
| Zanzalintinib + pembrolizumab maintenance ([NCT07845786](https://clinicaltrials.gov/study/NCT07845786){target="_blank" rel="noopener"}) | Not yet recruiting; 60 estimated (registered 2026-09-29) | Single-arm phase II after carboplatin plus paclitaxel or nab-paclitaxel plus pembrolizumab induction in metastatic squamous NSCLC | PFS at 6 months | Second single-arm multikinase-inhibitor maintenance study alongside NCT05613413; no randomized control, and antiangiogenic bleeding risk is again a squamous-specific safety question |
Duration trials are unusually valuable because indefinite-treatment conventions can persist without randomized evidence. Overall survival, quality of life, immune toxicity, retreatment, cost, and time off treatment all belong in the endpoint set.
Can an experimental first-line combination beat pembrolizumab plus chemotherapy in squamous disease?¶
| Trial | Status; planned enrollment | Design signal | Primary question | Interpretation boundary |
|---|---|---|---|---|
| ABBV-1480 + chemotherapy vs pembrolizumab + chemotherapy ([NCT07756645](https://clinicaltrials.gov/study/NCT07756645){target="_blank" rel="noopener"}) | Recruiting; 940 estimated (first posted 2026-08-10; last update 2026-10-20) | Open-label randomized phase III in previously untreated stage IIIB/IIIC/IV squamous NSCLC not amenable to cure; dual primary PFS (BICR, RECIST 1.1) and OS | Whether adding ABBV-1480 to carboplatin plus paclitaxel or nab-paclitaxel improves PFS and OS versus a KEYNOTE-407-like control | Direct squamous first-line population (non-squamous histology is an exclusion). The live registry does not state ABBV-1480's mechanism; a PubMed search for the code name on 2026-10-24 returned no records, so none is inferred. Sites listed: United States and Puerto Rico |
Can treatment be molecularly assigned or adapted?¶
| Trial | Status; planned enrollment | Strategy | What would make it important |
|---|---|---|---|
| ctDNA-directed perioperative therapy ([NCT04966663](https://clinicaltrials.gov/study/NCT04966663){target="_blank" rel="noopener"}) | Recruiting; 66 estimated | Phase II uses ctDNA to assign therapy in lung cancer | Demonstrating that acting on molecular residual disease improves relapse-free survival, not merely predicts it |
| CLEAR-Lung III ([NCT07858253](https://clinicaltrials.gov/study/NCT07858253){target="_blank" rel="noopener"}) | Not yet recruiting; 43 estimated (registered 2026-10-05) | Phase II ctDNA/MRD-positive unresectable stage III NSCLC after concurrent chemoradiation; primary endpoint is MRD (ctDNA) clearance | A registered strategy trial, but small, not yet recruiting, and powered for molecular clearance rather than survival versus standard PACIFIC consolidation |
| DRP-104 in NFE2L2/KEAP1-altered NSCLC ([NCT07249372](https://clinicaltrials.gov/study/NCT07249372){target="_blank" rel="noopener"}) | Recruiting; 37 estimated | Phase II glutamine-antagonist strategy; ORR primary | Directly targets an adverse, metabolically rewired genotype enriched in LUSC; needs durability and safety beyond response |
| Afatinib + prednisone ([NCT04497584](https://clinicaltrials.gov/study/NCT04497584){target="_blank" rel="noopener"}) | Active, not recruiting; 12 actual | Phase II in previously treated advanced squamous NSCLC | Tests whether toxicity modulation can widen an older ErbB strategy; sample size makes estimates imprecise |
ctDNA is already prognostic after resection, but treatment-predictive validation is the missing link ([PMID 37055640](https://pubmed.ncbi.nlm.nih.gov/37055640/){target="_blank" rel="noopener"}). NFE2L2/KEAP1 targeting is similarly rational but remains experimental; the alteration should qualify a patient for a trial, not for an unproven off-label metabolic therapy.
Can new antigen/payload combinations work in LUSC?¶
| Trial | Status; planned enrollment | Agent class | Key LUSC issue |
|---|---|---|---|
| PANKU-Lung05 ([NCT07739199](https://clinicaltrials.gov/study/NCT07739199){target="_blank" rel="noopener"}) | Not yet recruiting; 200 estimated | Phase II/III izalontamab brengitecan plus a PD-1/VEGF bispecific antibody vs carboplatin/paclitaxel plus the same bispecific antibody | Direct first-line advanced squamous population; the phase III primary endpoint is PFS, and the shared experimental bispecific in both arms means the comparison isolates the ADC-containing backbone rather than the entire regimen |
| HLX43 ± HLX07 vs docetaxel ([NCT07459751](https://clinicaltrials.gov/study/NCT07459751){target="_blank" rel="noopener"}) | Recruiting; 706 estimated | Phase II/III ADC alone or with EGFR antibody | Direct advanced/metastatic squamous population; OS and PFS primary outcomes are stronger than response alone |
| HDM2020 ([NCT07638891](https://clinicaltrials.gov/study/NCT07638891){target="_blank" rel="noopener"}) | Recruiting; 150 estimated | Phase I FGFR2b-directed ADC | Requires reproducible FGFR2b selection, therapeutic window, and proof that expression is sufficiently homogeneous |
| Enfortumab vedotin EV-202 ([NCT04225117](https://clinicaltrials.gov/study/NCT04225117){target="_blank" rel="noopener"}) | Active, not recruiting; 329 actual across cohorts | Nectin-4-directed ADC, with a pembrolizumab combination in a later cohort | Basket structure means lung-histology cohort data must be separated from pan-tumour totals |
ADC development cannot assume that a surface target is uniform or that payload sensitivity is histology-agnostic. TROPION-Lung01 is a warning: datopotamab deruxtecan improved PFS overall, but the squamous subgroup numerically favoured docetaxel for both PFS and OS ([PMID 39250535](https://pubmed.ncbi.nlm.nih.gov/39250535/){target="_blank" rel="noopener"}).
What comes after chemo-immunotherapy?¶
| Trial | Status; planned enrollment | Design | Why it matters |
|---|---|---|---|
| 7MW3711 vs docetaxel ([NCT07831863](https://clinicaltrials.gov/study/NCT07831863){target="_blank" rel="noopener"}) | Not yet recruiting; 600 estimated (registered 2026-09-21; China only) | Open-label randomized phase III in locally advanced/metastatic squamous NSCLC after platinum chemotherapy and immunotherapy; OS primary | A second squamous-specific randomized trial against docetaxel after platinum plus anti-PD-(L)1 therapy, alongside the HLX43 ± HLX07 phase II/III study ([NCT07459751](https://clinicaltrials.gov/study/NCT07459751){target="_blank" rel="noopener"}), whose record requires progression after first-line platinum plus anti-PD-1/PD-L1. The registry record does not state the agent's mechanism, and docetaxel is a weak comparator after taxane-containing first-line therapy |
Published prospective squamous-specific efficacy data after chemo-IO remain single-arm. For example, in WJOG14120L cisplatin/gemcitabine/necitumumab produced ORR 26.1% and missed its 40% target ([PMID 42816458](https://pubmed.ncbi.nlm.nih.gov/42816458/){target="_blank" rel="noopener"}).
Can immunity be personalized or rebuilt?¶
| Trial | Status; planned enrollment | Strategy | Central uncertainty |
|---|---|---|---|
| V940-013 ([NCT07221474](https://clinicaltrials.gov/study/NCT07221474){target="_blank" rel="noopener"}) | Recruiting; 180 estimated across 11 countries listed | Personalized neoantigen vaccine intismeran autogene/placebo plus pembrolizumab and carboplatin/taxane | Manufacturing time, neoantigen quality, added benefit over a strong control, and accessibility |
| Cancer-specific CD8+ TIL therapy ([NCT05902520](https://clinicaltrials.gov/study/NCT05902520){target="_blank" rel="noopener"}) | Active, not recruiting; 18 estimated | Phase I selected tumour-infiltrating lymphocytes with low-dose IL-2 | Feasibility, lymphodepletion/IL-2 burden, antigen escape, and scalable manufacturing |
| PF-08634404 in early/locally advanced NSCLC ([NCT07489066](https://clinicaltrials.gov/study/NCT07489066){target="_blank" rel="noopener"}) | Recruiting; 120 estimated across 11 countries listed on 2026-10-17 (five on 2026-08-31) | Phase II monotherapy/combination development; surgical feasibility and pCR endpoints | Mechanism must improve cure without delaying or preventing surgery |
Personalization adds logistical endpoints that conventional drug trials can ignore: proportion successfully manufactured, time from biopsy to dose, dropout before infusion, representativeness of included patients, and cost per treated—not merely enrolled—participant.
Status is not evidence¶
| Registry label | What it means | What it does not mean |
|---|---|---|
| Recruiting | Sponsor reports at least one recruiting site/cohort | Every listed site has capacity, the LUSC cohort is open, or the therapy works |
| Active, not recruiting | Intervention/follow-up continues without new enrollment | Results are mature or publicly available |
| Completed | Protocol-defined participation ended | Results are posted, peer reviewed, positive, or practice changing |
| Terminated | Study stopped early | The drug necessarily lacked efficacy; inspect reason, exposure, and data |
| Unknown | Status not recently verified under registry rules | Trial is definitely closed |
| Withdrawn | Stopped before enrollment | Biological hypothesis was disproven |
Trial matching checklist¶
- Confirm pathology and whether mixed/adenosquamous histology is allowed.
- Record TNM descriptors, edition, resectability, measurable disease, and all metastatic sites.
- Complete the molecular assay required by the trial, including exact variant and central confirmation rules.
- Build a line-by-line treatment history: agents, dates, best response, progression pattern, and grade ≥3 toxicity.
- Review brain metastases, steroids, autoimmune disease, transplant, interstitial lung disease, infection, and anticoagulation.
- Check haemoptysis, cavitation, major-vessel invasion, and fistula risk for antiangiogenic or some ADC programs.
- Verify ECOG status, renal/hepatic/marrow function, ECG, pulmonary function, and washout intervals.
- Ask whether the control arm is a reasonable current option for this individual.
- Verify cohort status and slot with the site; do not rely only on overall registry status.
- Discuss travel, biopsies, blood draws, hospitalization, contraception, caregiver burden, and financial toxicity.
Endpoint literacy¶
| Endpoint | Useful for | Vulnerability |
|---|---|---|
| ORR | Early antitumour activity | Can be brief; ignores stable disease, toxicity, and survival |
| PFS | Delaying progression/death | Scan timing, censoring, and pseudoprogression can influence it |
| EFS | Curative-intent multimodality sequence | Definitions include different pre/postoperative events across trials |
| pCR/MPR | Rapid perioperative signal | Surrogacy for OS is not perfect; pathology processing must be standardized |
| OS | Patient-important and hard to dispute | Requires time and is diluted by crossover/subsequent therapy |
| ctDNA clearance | Sensitive biological response | Assay- and shedding-dependent; treatment-guided utility unproven |
| PRO/QoL | Function and lived net benefit | Missing data are often informative rather than random |
| Feasibility | Surgery/manufacturing/delivery success | Must count all enrolled or intended patients, not only treated completers |
Portfolio gaps¶
- LUSC-specific trials for older, frail, ECOG 2–3, COPD, autoimmune, and transplant populations remain sparse.
- Central-airway obstruction, cavitation, and bleeding risk are usually exclusions or safety variables, not primary research questions.
- Few trials randomize ctDNA-guided escalation or de-escalation.
- The marginal value of adjuvant checkpoint blockade after neoadjuvant pCR remains unisolated.
- ADC programs need prospective histology interaction and target-heterogeneity studies.
- Patient-reported breathlessness, cough, haemoptysis fear, cognition, caregiver burden, and treatment time are inconsistently prioritized.
- Global participation does not guarantee representative access within countries or among rural and lower-income patients.
Open questions¶
- Can NFE2L2/KEAP1-directed metabolic therapy convert an immune-resistant state without prohibitive systemic toxicity?
- Which surface antigen is sufficiently homogeneous and tumour-selective for a durable LUSC ADC?
- Can MRD-guided treatment reduce recurrence and spare MRD-negative patients unnecessary therapy?
- What is the minimum effective duration of maintenance immunotherapy after chemo-immunotherapy response?
- Can platform trials report completed negative hypotheses as visibly as positive substudies?
Related pages¶
- Failed and frontier targets
- Molecular landscape
- Biomarkers
- Early-stage and perioperative therapy
- Systemic therapy
References¶
- ClinicalTrials.gov. CheckMate 017. [NCT01642004](https://clinicaltrials.gov/study/NCT01642004){target="_blank" rel="noopener"}
- ClinicalTrials.gov. KEYNOTE-407. [NCT02775435](https://clinicaltrials.gov/study/NCT02775435){target="_blank" rel="noopener"}
- ClinicalTrials.gov. CheckMate 816. [NCT02998528](https://clinicaltrials.gov/study/NCT02998528){target="_blank" rel="noopener"}
- ClinicalTrials.gov. KEYNOTE-671. [NCT03425643](https://clinicaltrials.gov/study/NCT03425643){target="_blank" rel="noopener"}
- ClinicalTrials.gov. AEGEAN. [NCT03800134](https://clinicaltrials.gov/study/NCT03800134){target="_blank" rel="noopener"}
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- ClinicalTrials.gov. PACIFIC. [NCT02125461](https://clinicaltrials.gov/study/NCT02125461){target="_blank" rel="noopener"}
- ClinicalTrials.gov. IMpower010. [NCT02486718](https://clinicaltrials.gov/study/NCT02486718){target="_blank" rel="noopener"}
- ClinicalTrials.gov. PEARLS/KEYNOTE-091. [NCT02504372](https://clinicaltrials.gov/study/NCT02504372){target="_blank" rel="noopener"}
- ClinicalTrials.gov. Lung-MAP master protocol. [NCT02154490](https://clinicaltrials.gov/study/NCT02154490){target="_blank" rel="noopener"}
- ClinicalTrials.gov. Cabozantinib/nivolumab Lung-MAP-related study. [NCT04310007](https://clinicaltrials.gov/study/NCT04310007){target="_blank" rel="noopener"}
- ClinicalTrials.gov. ctDNA-directed lung-cancer therapy. [NCT04966663](https://clinicaltrials.gov/study/NCT04966663){target="_blank" rel="noopener"}
- ClinicalTrials.gov. Cabozantinib plus pembrolizumab maintenance. [NCT05613413](https://clinicaltrials.gov/study/NCT05613413){target="_blank" rel="noopener"}
- ClinicalTrials.gov. V940-013 personalized vaccine study. [NCT07221474](https://clinicaltrials.gov/study/NCT07221474){target="_blank" rel="noopener"}
- ClinicalTrials.gov. DRP-104 in NFE2L2/KEAP1-altered NSCLC. [NCT07249372](https://clinicaltrials.gov/study/NCT07249372){target="_blank" rel="noopener"}
- ClinicalTrials.gov. HLX43 ± HLX07 in advanced squamous NSCLC. [NCT07459751](https://clinicaltrials.gov/study/NCT07459751){target="_blank" rel="noopener"}
- ClinicalTrials.gov. PANKU-Lung05. [NCT07739199](https://clinicaltrials.gov/study/NCT07739199){target="_blank" rel="noopener"}
- ClinicalTrials.gov. HDM2020 FGFR2b ADC. [NCT07638891](https://clinicaltrials.gov/study/NCT07638891){target="_blank" rel="noopener"}
- ClinicalTrials.gov. DIAL maintenance-duration trial. [NCT05255302](https://clinicaltrials.gov/study/NCT05255302){target="_blank" rel="noopener"}
- ClinicalTrials.gov. Cancer-specific CD8+ TIL therapy. [NCT05902520](https://clinicaltrials.gov/study/NCT05902520){target="_blank" rel="noopener"}
- ClinicalTrials.gov. EV-202 enfortumab vedotin basket study. [NCT04225117](https://clinicaltrials.gov/study/NCT04225117){target="_blank" rel="noopener"}
- ClinicalTrials.gov. Afatinib plus prednisone in squamous NSCLC. [NCT04497584](https://clinicaltrials.gov/study/NCT04497584){target="_blank" rel="noopener"}
- ClinicalTrials.gov. Symbiotic-Lung-10. [NCT07489066](https://clinicaltrials.gov/study/NCT07489066){target="_blank" rel="noopener"}
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- ClinicalTrials.gov. Zanzalintinib plus pembrolizumab first-line maintenance in metastatic squamous NSCLC. [NCT07845786](https://clinicaltrials.gov/study/NCT07845786){target="_blank" rel="noopener"}
- ClinicalTrials.gov. 7MW3711 versus docetaxel after chemoimmunotherapy in squamous NSCLC. [NCT07831863](https://clinicaltrials.gov/study/NCT07831863){target="_blank" rel="noopener"}
-
Yoshioka H, Mori K, Ishikawa N, Kanemura H, Azuma K, Toi Y, et al. Phase II Study of Cisplatin/Gemcitabine Plus Necitumumab for Squamous NSCLC After ICI-Platinum Therapy (WJOG14120L). Cancer Sci. 2026. PMID 42816458
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Daly ME, Simone CB 2nd, Redman MW, et al. Induction and consolidation atezolizumab with stereotactic body radiation therapy versus radiation alone in high-risk, early-stage non-small-cell lung cancer (SWOG/NRG S1914): a multicentre, open-label, superiority, phase 3, randomised controlled trial. Lancet. 2026;408(10562):1313-1325. PMID 42702214. Catalogue/retrieval priority; full-text synthesis pending.
- ClinicalTrials.gov. S1914: Atezolizumab with stereotactic body radiation therapy versus stereotactic body radiation therapy alone. [NCT04214262](https://clinicaltrials.gov/study/NCT04214262){target="_blank" rel="noopener"}. API v2, accessed 2026-10-24.
- ClinicalTrials.gov. ABBV-1480 combined with chemotherapy versus pembrolizumab combined with chemotherapy for first-line locally advanced or metastatic squamous NSCLC. [NCT07756645](https://clinicaltrials.gov/study/NCT07756645){target="_blank" rel="noopener"}. API v2, accessed 2026-10-24.
- ClinicalTrials.gov. CLEAR-Lung III: circulating tumor DNA-guided consolidation chemotherapy and immunotherapy after chemoradiation in unresectable stage III NSCLC. [NCT07858253](https://clinicaltrials.gov/study/NCT07858253){target="_blank" rel="noopener"}. API v2, accessed 2026-10-24.