Sacituzumab Tirumotecan in EGFR-Resistant NSCLC: A Two-Layer Integrity Analysis
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BBIU – October 2025
References: NEJM (doi:10.1056/NEJMoa2512071), ClinicalTrials.gov (NCT04152499, NCT05870319)
Part I – The NEJM Article (NEJMoa2512071)
Executive Summary
The New England Journal of Medicine recently published the study of sacituzumab tirumotecan (SKB264, TROP2-ADC) in patients with EGFR-mutated, EGFR-TKI–resistant advanced NSCLC.
The reported results show meaningful response rates and survival outcomes in this heavily pretreated population. Clinically, the article positions SKB264 as a new therapeutic option in a setting with limited alternatives.
Yet, the trial design presents a structural weakness:
TROP2 expression was not required for enrollment.
Tissue was collected but biomarker assessment is performed retrospectively.
The authors briefly acknowledge this in the discussion, framing it as a limitation rather than a methodological flaw.
Five Laws of Epistemic Integrity
Truthfulness — Moderate: Trial registry and article confirm lack of prospective biomarker selection.
Reference — Moderate: Sources are cited, but the limitation is downplayed.
Reliability — Low: Without prospective stratification, efficacy signals are diluted.
Judgment — Low: NEJM prioritized impact (new option in EGFR-TKI resistance) over design rigor.
Inference Traceability — Low: Conclusions on efficacy irrespective of TROP2 cannot be causally traced.
BBIU Opinion
The publication validates SKB264 symbolically, yet its scientific solidity is questionable. The absence of biomarker-driven selection undermines interpretability. NEJM’s editorial choice reflects the political economy of high-impact oncology journals, where novelty and unmet need often override strict methodological discipline.
Part II – Phase I/II Evidence (NCT04152499) and Our Discussion
Findings from Early-Phase Trials
NCT04152499 (KL264-01, MK-2870-001):
Officially Phase I/II, first-in-human, started 2020.
Planned enrollment: 1,410 patients, unusually large for FIH.
Design: non-randomized, multicentric, multiple expansion cohorts across >100 centers (U.S., Europe, Asia).
Indications: multiple epithelial cancers (breast, ovarian, NSCLC, gastric, SCLC, urothelial, etc.).
No TROP2 confirmation required for entry, tissue requested only for retrospective analysis.
Results (published in PubMed/ASCO 2023–24):
ORR ~40% overall in NSCLC, higher (~55%) in EGFR-mutated subgroup.
Median PFS ~6–11 months depending on cohort.
Safety: hematologic toxicity, occasional interstitial lung disease.
Phase II expansion (SKB264-II-08):
NSCLC EGFR-mutated (n≈64).
ORR ~34%, median PFS ~9.3 months.
Again, no prospective TROP2 stratification.
Discussion Highlights
Unusual scale: 1,410 patients for a Phase I/II is atypical; essentially an umbrella platform trial.
Global early-phase vs China-only pivotal: Paradox that early phases were global and large, while Phase III (NCT05870319) is restricted to China with only ~356–480 patients.
Biomarker paradox:
ADC mechanism depends on TROP2.
Standard practice in NSCLC already includes biopsy and molecular profiling.
Yet sponsor chose not to require TROP2 confirmation for entry.
Strategic logic:
Avoid delays of companion diagnostic validation.
Maximize market by claiming efficacy in “all-comers.”
Possibly rely on bystander effect to justify activity even in TROP2-low tumors.
Risk:
Data less reliable, diluted efficacy signal, limited credibility with FDA/EMA.
Ethical concern: exposing patients without target to ADC toxicity.
BBIU Opinion
The Phase I/II program is scientifically weak despite being large and multicentric. Its design prioritizes speed and breadth over precision. The later restriction to China-only Phase III indicates a regulatory shortcut aimed at NMPA approval, not global harmonization.
This creates an integrity gap: a drug developed globally, tested broadly, but pivotally validated only in China without biomarker stratification.
BBIU Critical Observations on SKB264 Clinical Development
1. Ethical Integrity Breach
No prospective confirmation of TROP2, despite being the drug’s molecular target.
Patients potentially lacking TROP2 expression were exposed to investigational toxicity without reasonable chance of benefit.
This violates the principle of risk–benefit balance (Declaration of Helsinki, CIOMS).
Physicians participated in trials where basic diagnostic standards (biopsy-based confirmation before systemic therapy) were disregarded.
2. Methodological Weakness
Phase I/II platform (NCT04152499) inflated to >1,400 planned subjects across >100 centers, but publications report <10% of participants.
Expansion cohorts fragmented, allowing only positive subsets to be highlighted (selective reporting).
Retrospective biomarker analysis prevents causal inference and undermines statistical validity.
3. Flawed Inclusion Criteria
Inclusion allowed all-comers with epithelial cancers (breast, ovarian, NSCLC, gastric, SCLC, urothelial), regardless of TROP2 expression.
This design dilutes efficacy signals and creates ethical risk.
The absence of biomarker-driven stratification in an ADC trial is a fundamental design flaw.
4. Risk of Data Manipulation
Large gap between enrollment declared and participants reported in publications leaves space for statistical cherry-picking.
Selective timing of publication (positive cohorts fast-tracked to NEJM/Nat Med; negative data unpublished or delayed) distorts the scientific narrative.
Control of data access by sponsor employees/stakeholders raises conflict-of-interest concerns.
5. Irregular Site Selection & Transparency Gap
Phase I/II: multicentric and global (U.S., Europe, Asia), ostensibly to enhance legitimacy.
Phase III pivotal (NCT05870319): restricted to China only, with ~356–480 patients.
This creates a paradox: early-phase exploratory data were international, but confirmatory pivotal evidence is generated in a single jurisdiction with lower regulatory transparency.
Limits external validity and raises doubts about acceptance by FDA/EMA.
BBIU Verdict
The SKB264 clinical program exhibits systemic weaknesses across ethics, methodology, inclusion design, data integrity, and site transparency.
Ethical safeguards were compromised.
Methodological rigor was sacrificed in favor of speed and market positioning.
Data reporting practices and trial asymmetry (global early-phase vs China-only pivotal) open space for manipulation and narrative control.
Integrity Assessment: Low — The program provides signals of activity but cannot be considered reliable or ethically robust evidence for global approval.
References
NEJM Article
Sacituzumab Tirumotecan in EGFR-TKI–Resistant, EGFR-Mutated Advanced NSCLC.
NEJM 2025; doi:10.1056/NEJMoa2512071.
Phase I/II Clinical Trial Registry
ClinicalTrials.gov Identifier: NCT04152499
Title: Phase I-II, First-in-Human Study of SKB264 (KL264-01/MK-2870-001) in Advanced Unresectable or Metastatic Solid Tumors.
Enrollment: 1,410 (planned). Start date: Feb 2020.
Phase III Clinical Trial Registry
ClinicalTrials.gov Identifier: NCT05870319
Title: A Phase III Study of SKB264 for EGFR Mutant NSCLC after EGFR-TKI Resistance.
Enrollment: ~356–480 (planned). Start date: Jun 2023.
Phase I/II Data Publication (NSCLC)
Zhao S., Cheng Y., Wang Q., Li X., Liao J., Rodon J., Meng X., Luo Y., Chen Z., Wang W., Yi T., Li Y., Yin Y., Xu H., Yu G., Mi Y., Fan Y., Wainberg Z., Wang X., Su C., Yu Q., Lai S., Sun L., Zhuang W., Wang X., Yang J., Li Y., Ge J., Li J., Zhang L., Fang W.
Sacituzumab tirumotecan in advanced non-small-cell lung cancer with or without EGFR mutations: phase 1/2 and phase 2 trials.
Nat Med 2025; doi:10.1038/s41591-025-03638-2. PMID: 40210967.
Phase I/II Data Publication (Breast Cancer and Solid Tumors)
Ouyang Q., et al.
First-in-Human Study of SKB264 (sacituzumab tirumotecan) in Breast Cancer and Solid Tumors.
J Hematol Oncol 2025.
PDF: 13045_2025_Article_1705.pdf (uploaded document).
Sponsor Disclosures
Conflict of interest statements within Nat Med article (Zhao et al. 2025): Employees/stakeholders of Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd.
Annex 1 — BBIU Regulatory Due-Diligence Checklist for ADC Trials
1. Companion Diagnostic Validation
Requirement: Prospective confirmation of target expression (TROP2) before enrollment.
Rationale: Ensures patients are not exposed to toxicity without molecular target; aligns with global standards (HER2, CLDN18.2).
Action: Develop and validate a companion diagnostic assay (IHC or alternative), harmonized across trial sites.
2. Biomarker-Driven Trial Design
Requirement: Stratification by target expression (TROP2-high vs TROP2-low/negative).
Rationale: Enables causal inference between target expression and drug efficacy.
Action: Primary endpoint analysis must be prespecified by biomarker subgroup.
3. Transparent Enrollment Reporting
Requirement: Publication of the full enrolled population, not only selective cohorts.
Rationale: Prevents selective reporting and data manipulation; provides reliable denominator for efficacy/safety rates.
Action: Registry updates must match published data, with full patient disposition tables.
4. Multinational Pivotal Trials
Requirement: Phase III must include diverse populations beyond a single country.
Rationale: Improves external validity and credibility with FDA/EMA; avoids reliance on single-jurisdiction regulatory leniency.
Action: Minimum three-region enrollment (Asia, U.S., EU).
5. Conflict-of-Interest Management
Requirement: Disclosure of investigator–sponsor relationships and separation of data analysis from sponsor-employed statisticians.
Rationale: Protects integrity of results; reduces bias in interpretation.
Action: Independent data monitoring committee (IDMC) with authority to audit trial conduct.
6. Ethical Oversight
Requirement: Strict adherence to risk–benefit principle; no enrollment without biomarker target if drug mechanism is target-dependent.
Rationale: Protects patient rights and aligns with Declaration of Helsinki.
Action: Ethics boards should reject protocols without prospective target confirmation.
Annex 2 — Ethical Violations and Patient Rights Breaches in SKB264 Trials
1. Violation of the Right to Informed Consent
Issue: Patients were not informed that TROP2 confirmation was absent at enrollment.
Impact: Some participants may have received the investigational drug without any realistic chance of benefit.
Breach: Undermines the ethical requirement of full disclosure and honest communication of expected outcomes.
2. Violation of the Right to Standard of Care
Issue: Biopsy and molecular profiling are global standard practice in NSCLC and epithelial cancers before systemic therapy.
Impact: Patients were treated without the inclusion of a biomarker test that could have been incorporated into existing diagnostic workflows.
Breach: Denies participants the diagnostic rigor routinely applied in non-trial settings.
3. Violation of the Right to Protection from Unnecessary Harm
Issue: TROP2-negative patients, unknowingly included, were exposed to hematologic toxicity and risk of interstitial lung disease.
Impact: Exposure to risk without corresponding benefit is prohibited under risk–benefit balance principles.
Breach: Contradicts the Declaration of Helsinki and CIOMS guidelines for patient safety.
4. Violation of the Right to Scientific Integrity
Issue: Enrollment far exceeded the number of patients published; cohorts were selectively reported.
Impact: Patients’ data are being used strategically, not transparently, diminishing the scientific value of their participation.
Breach: Betrays the trust of patients who assume their contribution advances verifiable science.
5. Violation of the Right to Equal Treatment Across Jurisdictions
Issue: Early-phase enrollment was multinational, yet the pivotal Phase III trial is restricted to China only.
Impact: Patients outside China contributed to drug development but may never benefit from regulatory approval in their countries.
Breach: Creates inequity in how participant contributions are valued and used.
BBIU Ethical Verdict
The SKB264 program demonstrates systemic ethical lapses:
Patients’ rights to informed consent, standard of care, protection from harm, scientific integrity, and equal treatment were all compromised.
A central paradox emerges with the FDA’s role:
The FDA accepted the sponsor’s IND application and allowed phase 1/2 trials in the U.S. with retrospective TROP2 confirmation, under the rationale that early exploratory studies can proceed without companion diagnostics.
However, this regulatory flexibility—intended for preliminary exploration—was leveraged by the sponsor to justify exposing patients globally to a TROP2-targeted ADC without verifying the presence of the target.
While legally permissible, this undermined ethical safeguards, since biopsy and molecular confirmation are already standard practice in NSCLC and other carcinomas.
This reveals a dual failure:
Regulatory loophole exploitation by the sponsor.
Ethical complacency from investigators and oversight boards that accepted a design where patients faced toxicity without guaranteed biological rationale.
Final Assessment:
This constitutes a serious ethical failure, where sponsor priorities and regulatory shortcuts—not only in China but also in the U.S. under FDA IND flexibility—outweighed patient protection.
