Colorectal & lung surface targets, prioritised for ADC and TCE, split by maturity.

TNFSF12/TWEAK-Fn14 axis is the best-validated novel target in this cohort with multiple 2026 primary research publications. Stromal TWEAK activates cancer cell Fn14 via NF-kB, promoting invasion, migration, and immune evasion. Clinical correlation with tumour size and stage validated in 235 human LUAD specimens. Antibody-tractable via receptor (Fn14). Anti-TWEAK mAb (RG7212) has been tested preclinically. White-space in NSCLC.

CDCP1 is a validated cell-surface tumour antigen with active ADC/CAR-T programs and complete white-space in SCLC. INVEST based on tractability and first-mover potential. Key de-risking data needed: SCLC IHC expression profiling.

CCK2R is the most compelling novel SCLC target in this cohort with SCLC-specific expression data, first clinical case, and planned trial. Its GPCR druggability and radiotheranostic precedent de-risk development. Phase 1 efficacy data would most change this assessment.

P2RY2 is a breakthrough discovery as a purinergic immune checkpoint with compelling preclinical data across multiple tumour types including CRC. However, evidence is very recent (preprint/2026 publication), no clinical-grade compound exists, and independent replication is needed. Peer-reviewed replication and clinical compound development would upgrade to INVEST.

SEZ6L is a validated SCLC surface target with strong subtype-specific expression and ADC feasibility. The key open question is whether it addresses patients distinct from SEZ6 and DLL3 programs. Clinical-stage ADC data would most change this assessment.

SLC7A5/LAT1 is overexpressed in NSCLC with strong metabolic rationale (mTORC1 activation via leucine transport). JPH203 inhibitor in early clinical. 211At-labelled radiopharmaceuticals and PET imaging provide theranostic potential. No late-phase NSCLC trials yet. Selective clinical candidate with NSCLC data would upgrade.

EphA3 is tractable with clinical antibody precedent and emerging ICB biomarker data, but tumour-intrinsic role in NSCLC is limited. TME-targeting and biomarker studies could elevate this target.

TNFRSF1B/TNFR2 is an emerging immuno-oncology target with compelling Treg depletion biology and clinical-stage antibodies. However, SCLC-specific validation is entirely absent, making this a speculative but strategically interesting watch-list candidate. SCLC TME characterisation data showing TNFR2+ Treg enrichment would most change this assessment.

p75NTR has plausible neuroendocrine lineage biology for SCLC but no direct evidence. WATCH. IHC/scRNA-seq showing strong p75NTR expression in SCLC specimens would upgrade.

Claudin-class precedent but CLDN7-specific SCLC data lacking. WATCH pending antibody development.

TACSTD2 is the most clinically validated target in this set with FDA-approved ADCs. INVEST with high confidence. Differentiation comes from next-gen combinations, not de novo targeting. The target is settled; the contest is at the asset layer. The ASCO 2026 readout for Kelun/Merck's sac-TMT (SKB264/MK-2870) positions it as current best-in-class on payload, linker and tolerability, ahead of Dato-DXd (Daiichi/AZ) and Trodelvy (Gilead). The play is a superior ADC, not de novo targeting.

SEZ6 is the strongest emerging SCLC target with highest expression, 52-82% ORR in Phase 1, and AbbVie-backed Phase 3 advancement. INVEST driven by compelling clinical data, near-universal expression, and less crowded competitive landscape than B7-H3 or DLL3. Phase 3 OS readout will be pivotal.

Nectin-4 is the most clinically advanced target in this set with an FDA-approved ADC and active NSCLC expansion. Key question is NSCLC expression prevalence and patient selection. Nectin-4 ADCs are in Phase 1 in lung, but the target has not yet delivered outside urothelial cancer; treat NSCLC as unproven.

DLL3 is the most validated target in SCLC with FDA-approved therapy and Phase 3 OS benefit. INVEST verdict reflects exceptional tractability and disease impact, despite late timing for new entrants. New data on combination strategies or resistance mechanisms could further refine positioning.

CD276 is a highly tractable, broadly expressed NSCLC target with an accelerating clinical pipeline and emerging efficacy data. The INVEST verdict reflects strong tractability and timing, though scientific rationale is limited by absent human genetic causality. Phase II/III NSCLC-specific efficacy data would most significantly upgrade the assessment.

ERBB2 exon 20 insertion mutations are the most clinically validated nomination in this set, with FDA-approved therapy and Phase 3 programmes. Despite being a mutation class rather than a discrete target, the biology maps directly to HER2 and represents a clear INVEST opportunity. Key upcoming inflection: Beamion LUNG-2 Phase 3 readout for zongertinib as first-line therapy. HER2 is the best-known ADC target, but that franchise is in breast; HER2-expressing lung is a small subset. Differentiation now comes from bispecific ADCs, not another naked ADC. The HER2 TKIs (zongertinib and peers) are a different mechanism used in combination, not direct ADC competition.

CEACAM5 has the most clinically mature pipeline of the 8 candidates but single-agent efficacy has been disappointing. WATCH for Phase III M9140 readout and novel CAR-T approaches that may change the calculus.

ERBB3 has a validated therapeutic platform (approved ADC) but limited expression in SCLC (~10%). WATCH pending preclinical validation of combination strategies (SMARCA4i + HER3-DXd) and SCLC-specific expression profiling. Transition to INVEST requires demonstration of meaningful ERBB3 expression in a treatable SCLC subpopulation. Included for completeness, but HER3 has disappointed clinically so far (patritumab deruxtecan); see risks.

EGFR is the gold-standard NSCLC target with the highest possible scientific, tractability, and disease impact scores. INVEST verdict reflects exceptional validation, but commercial and timing scores are constrained by the saturated competitive landscape. New investment is justified only for highly differentiated resistance-specific or novel-modality programs. Input signal flags (Flag_overhype, Flag_low_consensus) are consistent with this saturated but validated profile. Relevant in both lung (mutant, TKI-driven) and colorectal (RAS-wild-type, cetuximab/panitumumab). Its many approved agents are TKIs and antibodies, not ADCs, so there is genuine whitespace for an EGFR ADC; TKIs are also limited by universal acquired resistance and lack a conjugate's bystander effect.

CDH17 is a translationally mature surface antigen with near-universal CRC expression, validated oncogenic mechanism, and a diverse pipeline of therapeutic modalities entering Phase I clinical trials. The key data gap is clinical efficacy proof-of-concept, expected from BI 905711 and CAR-T trial readouts within 12-18 months. Near-universal CRC expression with a diverse pipeline (ADCs, CAR-T, bispecifics); the gap is CRC efficacy proof-of-concept (BI 905711; 7MW4911 ADC showed 71-99% tumour-growth inhibition preclinically).

GUCY2C is the most clinically de-risked target in this cohort, with Phase I CAR-T data showing meaningful ORRs in mCRC. INVEST based on clinical signal, lineage-restricted expression, and dual vaccine/therapeutic strategy. Key next data: IM96 dose expansion and universal CAR-T trial results.

MUC16 is tractable with multiple modalities and a validated surface antigen with emerging NSCLC data. Bispecific and ADC programs advancing. Key data gap is NSCLC-specific clinical efficacy.

GPA33 combines near-universal CRC expression with a wide-open competitive landscape and novel modalities (CAR-M, radioimmunotherapy). INVEST based on early-mover advantage and excellent target biology, though very early clinical stage adds risk. SNA028 trial and CAR-M data are the key upcoming milestones.

MET is the strongest INVEST target in this cohort. Recent SCLC-specific data demonstrate therapeutic benefit of MET inhibition in combination with CIT, leveraging an established and well-tolerated drug class. The key next step is a clinical trial of MET inhibitor + CIT in ES-SCLC with HGF/MET biomarker stratification. Value is likely in combination, e.g. the AbbVie MET ADC (telisotuzumab vedotin) plus osimertinib, rather than monotherapy.